阅读说明：本技术 苯并呋喃类化合物的制备方法 (Preparation method of benzofuran compound ) 是由 祝诗发 张玲 曹同祥 王永东 黄志鹏 于 2019-10-17 设计创作，主要内容包括：本发明公开了一种苯并呋喃类化合物的制备方法。该制备方法是：具有式(I)结构的化合物在催化剂条件下发生反应,得到如式(Ⅱ)的苯并呋喃类化合物。本发明方法可以在温和的反应条件下同时构建苯环与呋喃环制备得到苯并呋喃类化合物,操作简单,步骤简便,原子利用率高达100％,而且式(I)结构的化合物可以从廉价易得的曲酸或麦芽酚简单衍生而来,成本低廉,给天然产物以及药物前体的制备提供一条新的、高效、低成本的途径。<Image he="251" wi="700" file="DDA0002238068900000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a preparation method of benzofuran compounds. The preparation method comprises the following steps: reacting the compound with the structure shown in the formula (I) under the condition of a catalyst to obtain the benzofuran compound shown in the formula (II). The method can simultaneously construct the benzene ring and the furan ring under mild reaction conditions to prepare the benzofuran compound, has simple operation and simple and convenient steps, has atom utilization rate as high as 100 percent, and can simply derive the compound with the structure shown in the formula (I) from kojic acid or maltol which is cheap and easy to obtainThe method has the advantages of low cost, and provides a new, efficient and low-cost way for preparing natural products and prodrugs.)

1. A preparation method of benzofuran compounds is characterized in that compounds shown in formula (I) react under the action of a catalyst to obtain the benzofuran compounds shown in formula (II):

wherein R is²Selected from hydrogen, trialkylsilyl, substituted or unsubstituted aryl or heteroaryl, C1-C13 linear or branched alkyl or heteroalkyl, C3-C10 cycloalkyl or heterocycloalkyl; r³Selected from hydrogen, hydroxy, C1-C6 straight or branched alkoxy;

when n is 1, m is 0, and R¹Selected from hydrogen, substituted or unsubstituted aryl; r⁴Selected from substituted or unsubstituted C1-C6 straight or branched chain alkyl or heteroalkyl, substituted or unsubstitutedPhenylthio, R⁶Is R⁴，R⁵Is hydroxy, R⁷Is R¹；

When n is 0, m is 1, and R is¹Selected from hydrogen, substituted or unsubstituted C1-C6 straight or branched alkyl or heteroalkyl, R⁵Is R⁴And are both hydrogen, R⁶Is R¹，R⁷Is a hydroxyl group;

when the group contains substituent groups, the substituent groups can be one or more, and each substituent group is independently selected from C1-C6 straight-chain or branched-chain alkyl, halogen, C1-C6 straight-chain or branched-chain alkoxy, cyano, amino, hydroxyl, ester group, alkenyl, alkynyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, substituted or unsubstituted aryl or heteroaryl;

the catalyst is a metal catalyst, and the metal is Fe, Yb, Sn, Bi, In, Sc, Ag, Zn, Cu and Pd.

2. The process according to claim 1, wherein the compound of formula (I) is prepared by reacting a compound of formula (I)

3. The method according to claim 1 or 2, wherein R is²Selected from hydrogen, substituted or unsubstituted aryl, C1-C13 straight or branched chain alkyl, C3-C6 cycloalkyl, thienyl; r³Selected from hydrogen, C1-C6 straight or branched chain alkoxy.

4. The method of claim 1 or 2, wherein the catalyst is an In, Ag, Sc, or Pd catalyst.

5. The preparation method according to claim 1 or 2Process, characterized in that the catalyst is Pd (PPh)₃)₄、AgBF₄、In(OTf)₃、Sc(OTf)₃、Pd(CH₃CN)₂Cl₂Or Pd (CF)₃CO₂)₂。

6. The method according to claim 1, wherein the reaction temperature is 0 to 100 ℃.

7. The preparation method according to claim 1 or 2, wherein the molar ratio of the catalyst to the compound of formula (I) is 1:100 to 1: 2.

8. The process according to claim 1 or 2, wherein the reaction solvent is one or a mixture of two or more selected from the group consisting of dichloroethane, tetrahydrofuran, 1, 4-dioxane, dichloromethane, acetonitrile, methanol, water, triethylamine, dimethylformamide, n-hexane, ethyl acetate, and hydrochloric acid.

Technical Field

The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a preparation method of benzofuran compounds.

Background

Benzofuran compounds and their derivatives, in particular hydroxybenzofurans, have a variety of biological activities (Al-Maharik, N. (2019), of antagonism of natural products of natural origin, including agonistic receptors of thyroid hormone, hormone receptor, β), and are important intermediates for pharmaceutical and organic synthesis (Xu, z.; Zhao, s.; Lv, z.; Feng, l.; Wang, y.; Zhang, f.; Bai, l.; ding, J. (2019), bezofuran derivatives and the same-tubocular, anti-bacterial activities₃Receptors and histone deacetylase inhibitors, which play important roles as antitumor drugs, cardiovascular drugs, nervous system drugs, anti-infective drugs, psychotropic drugs, digestive system drugs, and the like (see below).

Many benzofuran compounds show good biological activity, but the content of benzofuran compounds in natural products is low, the quantity of separation and extraction is limited, and the yield of benzofuran compounds cannot meet the demand. Therefore, the artificial synthesis of benzofuran compounds is very important.

Common processes FOR preparing BENZOFURAN Compounds are known to build furan rings by 4 types OF the following (METHODS FOR THE SYNTHESIS OF BENZOFURAN derivitives (revew), Chemistry OF heterocyclic Compounds, vol.33.no.1l, 1997):

for example, CN104478837B reports that a compound containing an o-bromophenylacetic acid structure and a compound containing a benzaldehyde structure are used as starting materials, and in the presence of alkali, a Perkin condensation reaction is performed to obtain a 2- (2-bromophenyl) -3-phenylpropenoic acid compound, and then under microwave, the 2- (2-bromophenyl) -3-phenylpropenoic acid compound is subjected to hydroxylation/intramolecular coupling/oxidative dehydrogenation reaction under the action of a catalyst and a ligand to obtain a 2-arylbenzofuran-3-carboxylic acid compound. CN104650018B reports that 1-sulfonyl-1, 2, 3-triazole compounds react under the catalysis of rhodium to obtain imine intermediates, and then palladium/carbon catalysts and 1atm H₂And continuously reacting under the action of the catalyst to obtain the 2, 3-disubstituted benzofuran derivative. CN105399710B reports that salicylaldehyde compounds and aryl acetonitrile compounds react under the conditions of catalysts and alkali to obtain 2-phenyl-3-cyano benzofuran compounds. CN106565648B reports that 2-allyl phenol compounds and iodine substituted fluorine-containing reagents are used as raw materials to synthesize fluorine-containing alkyl substituted 2, 3-dihydrobenzofuran derivatives in one step under the action of catalysts, ligands and alkali. Although many reports are provided in the prior art for preparing benzofuran compounds, most methods are based on a substituted benzene ring to reconstruct furan rings (university of vinblastic science, thesis of synthesis of polysubstituted benzofuran compounds, bunyleli, 2012), and the reaction is limited, and no report is provided for constructing benzene rings and furan rings.

By using conventional synthetic methods, many routes for preparing natural products or prodrugs are complicated in steps, complex in operation, harsh in conditions and low in overall yield. For example, the literature (Synthesis,2016,48, A-J) reports the total Synthesis of the natural product Cuspidan B, which takes 1, 3-cyclohexanedione as a raw material, and takes 21 percent of total yield through 7 steps of reaction, while malodorous dimethyl sulfide is used, and a large amount of reagents and energy are consumed through protection/deprotection operations. The literature (Angew. chem. int. Ed.2011,50,6814-6818) reports the total synthesis of the PI3K kinase inhibitor Liphagal, starting from commercially available starting materials, in 19 steps with an overall yield of 0.95%, using noble metal catalysts in multiple steps, relatively intense microwave reaction conditions (250 ℃) and relatively long reaction times (up to 4 days in one step).

Disclosure of Invention

In order to solve the defects and shortcomings of the prior art, the invention aims to provide a preparation method of benzofuran compounds.

The purpose of the invention is realized by the following technical scheme: a preparation method of benzofuran compounds comprises the following steps of reacting compounds shown in a formula (I) in the presence of a catalyst to obtain the benzofuran compounds shown in a formula (II):

wherein R is²Selected from hydrogen, trialkylsilyl, substituted or unsubstituted aryl or heteroaryl, C1-C13 linear or branched alkyl or heteroalkyl, C3-C10 cycloalkyl or heterocycloalkyl; r³Selected from hydrogen, hydroxy, C1-C6 straight or branched alkoxy;

when n is 1, m is 0, and R¹Selected from hydrogen, substituted or unsubstituted aryl; r⁴Selected from the group consisting of substituted or unsubstituted C1-C6 straight or branched alkyl or heteroalkyl, substituted or unsubstituted phenylthio, R⁶Is R⁴，R⁵Is hydroxy, R⁷Is R¹；

When n is 0, m is 1, and R is¹Selected from hydrogen, substituted or unsubstituted C1-C6 straight or branched alkyl or heteroalkyl, R⁵Is R⁴And are both hydrogen, R⁶Is R¹，R⁷Is hydroxyA group;

when the group contains substituent groups, the substituent groups can be one or more, and each substituent group is independently selected from C1-C6 straight-chain or branched-chain alkyl, halogen, C1-C6 straight-chain or branched-chain alkoxy, cyano, amino, hydroxyl, ester group, alkenyl, alkynyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, substituted or unsubstituted aryl or heteroaryl;

the catalyst is a metal catalyst, and the metal is Fe, Yb, Sn, Bi, In, Sc, Ag, Zn, Cu and Pd.

The inventor finds that the compound with the structure of formula (I) can simultaneously construct a benzene ring and a furan ring under certain catalytic conditions to obtain the benzofuran compound. Presumably the reaction proceeds as follows:

the metal catalyst activates the carbon-carbon triple bond of the formula (I), then carbonyl attacks the activated carbon-carbon triple bond to form a furopyran salt intermediate, and the intermediate is subjected to ring opening and ring closing under reaction conditions and finally converted into a product of the formula (II).

As a preferred embodiment of the present invention, the compound of formula (I) may be prepared by compounding

And

obtained by a coupling reaction, R⁸Selected from hydroxy, triflate or halogen.

Common Fe, Yb, Sn, Bi, In, Sc, Ag, Zn, Cu, Pd-based catalysts including, but not limited to Pd (OAc)₂、PdCl₂、Pd(PPh₃)₄、Pd(dppf)Cl₂、Pd(PPh₃)Cl₂、Pd₂(dba)₃、Pd(dppp)Cl₂、 Pd(acac)2、Fe(OTf)₃、Yb(OTf)₃、Sn(OTf)₃、Bi(OTf)₃、In(OTf)₃、Sc(OTf)₃、AgBF₄、 ZnI、Cu(OTf)₂、Fe(OTf)₂、Pd(CH₃CN)₂Cl₂、Pd(CF₃CO₂)₂Etc. are suitable for the production method of the present invention. The inventors have tried various metal catalysts and found that all have a certain yield, and further, the catalyst is preferably an In, Ag, Sc or Pd catalyst. When the four metal catalysts are selected, the yield of the reaction can reach more than 50 percent.

More preferably, the catalyst is more preferably Pd (PPh)₃)₄、AgBF₄、In(OTf)₃、Sc(OTf)₃Pd(CH₃CN)₂Cl₂Or Pd (CF)₃CO₂)₂。

Preferably, the reaction temperature of the preparation method is 0-100 ℃.

Preferably, the molar ratio of the catalyst to the compound of formula (I) in the preparation method is 1: 100-1: 2.

Preferably, the solvent for reaction is selected from one or a mixture of two or more of dichloroethane, tetrahydrofuran, 1, 4-dioxane, dichloromethane, acetonitrile, methanol, water, triethylamine, dimethylformamide, n-hexane, ethyl acetate and hydrochloric acid.

In the present invention, the term "C1-C6 straight or branched chain alkyl group" means a straight or branched chain hydrocarbon group having 1 to 6 carbon atoms. Including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, sec-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, cyclopropane, cyclohexane and the like.

In the present invention, the term "C1-C6 linear or branched alkoxy" refers to a linear or branched O-alkyl group having 1 to 6 carbon atoms. Including but not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentyloxy, neopentyloxy, hexyloxy, and the like.

In the present invention, the term "halogen" refers to a halogen atom, including fluorine, chlorine, bromine and iodine.

In the present invention, the term "C3-C10 cycloalkyl" refers to a hydrocarbon group having 3 to 10 carbon atoms linked together to form a ring. Including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

The term "aryl" refers to any functional group or substituent derived from an aromatic ring (typically an aromatic hydrocarbon such as phenyl, naphthyl, biphenyl, indane, tetrahydronaphthyl, and the like), which may be unsubstituted or substituted one or more times.

In the present invention, the term "heterocyclic group" means a saturated or unsaturated monocyclic or bicyclic heterocyclic group having 5 to 10 ring-constituting atoms, in which 1 to 4N atoms and/or 1 to 4S atoms and/or 1 to 4O atoms may be present, and which may be substituted once, twice or more times by halogen, alkyl, alkoxy, aryl, cyano, amino, hydroxyl, ester, aldehyde and/or carbonyl groups, including but not limited to pyridyl, thienyl, furyl and the like.

The following are some examples of products which can be obtained according to the invention: disubstituted benzofurans (P1):

trisubstituted benzofurans (P2):

tetra-substituted benzofuran (P3):

natural products or potential drug molecules and their intermediates (P4):

compared with the prior art, the invention has the following beneficial effects:

the compound with the structure of the formula (I) can simultaneously construct a benzene ring and a furan ring under mild reaction conditions to prepare the benzofuran compound, the operation is simple, the steps are simple, the atom utilization rate is up to 100%, the compound with the structure of the formula (I) can be derived from kojic acid or maltol which are cheap and easy to obtain or are simply derived from the kojic acid or maltol, and the cost is low.

Detailed Description

Unless otherwise specified, the raw materials, reagents and solvents used in the present invention were all purchased commercially without any treatment. The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto.