CN116023357B - A method for converting o-hydroxyacetophenones into chromanone compounds containing quaternary carbon centers - Google Patents

Abstract

The invention discloses a synthesis method of directly reacting o-hydroxyacetophenones with dimethyl sulfoxide (DMSO) under the promotion of protonic acid to obtain a chromanone compound containing a quaternary carbon center, and belongs to the technical field of organic synthesis. Using o-hydroxyacetophenones as raw materials, sodium acetate and morpholine as additives, dimethyl sulfoxide is heated and activated under acidic conditions to provide diverse synthon reactions to obtain chromanone compounds containing a quaternary carbon center at the 3-position. This reaction does not require any metal catalyst, is simple to operate, has good reaction selectivity, has a good substrate application range, and has potential industrial application prospects.

Description

A method for converting o-hydroxyacetophenones into chromanone compounds containing quaternary carbon centers

Technical Field

The invention relates to a new synthesis method for converting o-hydroxyacetophenone into a chromanone compound containing a quaternary carbon center, and belongs to the technical field of organic synthesis.

Background technique

3-substituted chromanone compounds are an important class of organic intermediates that are widely found in natural products and molecular skeletons with biological and pharmaceutical activities. They have attracted more attention in the fields of organic chemistry and medicinal chemistry. In view of this, people have developed a series of synthetic methods for synthesizing this type of compounds starting from simple raw materials. Among them, the most common ones are substituted chromanone compounds starting from o-hydroxybenzaldehyde through various cyclization reactions. Recently, there have been many examples of reactions involving the activation of o-hydroxyacetophenone and dimethyl sulfoxide (DMSO). For example, DMSO provides a double synthon with o-hydroxyacetophenone under oxidant or acidic activation conditions to obtain a 3-substituted chromium. ketones

(Reaction 1, Chem. Commun., 2017, 53, 5346-5349 and Reaction 2, Svnthesis 2022, 54, 2185-2192) reactions have been studied more. However, DMSO activates and provides three synthons for the reaction to form a chromanone compound containing a quaternary carbon center at the 3-position. It may be that the product formed by the participation of two molecules of DMSO in the reaction continues to react with the third molecule of DMSO as steric hindrance. Large, it is difficult to obtain molecules containing quaternary carbon centers.

Summary of the invention

In view of the above technical problems, the present invention provides a simple raw material source, acetic acid directly activates dimethyl sulfoxide under metal-free catalytic conditions, and provides three different synthesis units to participate in the reaction to obtain a chromanone compound containing a quaternary carbon center at the 3-position New synthesis method. This method uses o-hydroxyacetophenones (Formula 1), which are easily available, as raw materials, and uses dimethyl sulfoxide and acetic acid as mixed solvents for a one-pot reaction to directly obtain chromanone substances containing a quaternary carbon center at the 3-position (Formula 2), it is simple to operate and has a wide range of substrate applications.

In order to achieve the above purpose, the embodiments of the present invention are as follows:

A method for preparing a chromanone compound containing a quaternary carbon center, which is characterized in that: using o-hydroxyacetophenone compounds (formula 1) as raw materials, under the action of sodium acetate and additives, dimethyl sulfoxide and acid are mixed The one-pot method of solvent heating is used to obtain the chromanone compound with the structure of formula (2) containing a quaternary carbon center.

Wherein, R represents hydrogen or a substituent, and n represents an integer of 0, 1, 2, 3 or 4.

In a preferred technical solution of the present invention, the molar ratio of the reactants of the o-hydroxyacetophenones compound (Formula 1) and dimethyl sulfoxide is 1:3.

In the preferred technical solution of the present invention, R represents hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, nitro, halogen, C ₁ -C ₆ alkyl Oxygen group, cyano group, amino group, sulfonic acid group, halogenated C ₁ -C ₆ alkyl group, C ₆ -C ₁₀ aryl group or 5-10 membered heteroaryl group.

In a preferred technical solution of the present invention, the acid is a common protonic acid, including formic acid, acetic acid, propionic acid, butyric acid, hydrochloric acid, phosphoric acid, and acetic acid.

In a preferred technical solution of the present invention, the additive is selected from amine compounds.

In a preferred technical solution of the present invention, the additive is selected from tetrahydropyrrole, morpholine, hexahydropiperidine, and proline.

In the preferred technical solution of the present invention, the reaction temperature is 110-140 degrees, and the reaction time is 10-30 hours.

In the preferred technical solution of the present invention, the specific steps of the reaction are:

Dissolve the o-hydroxyacetophenone compound shown in Formula 1 in dimethyl sulfoxide, then add sodium acetate, acid and additives, and react under heating conditions. After the reaction is complete, remove the solvent and additives in the reaction solution, and use organic The target product is extracted with a solvent, the organic phases are combined, dried, and rotary evaporated under reduced pressure to obtain a crude product, which is then chromatographed on silica gel to obtain a chromanone compound containing a quaternary carbon center having the structure of formula (2).

Furthermore, the reaction can be carried out under nitrogen, air, oxygen and other gas conditions. After the reaction is completed, the product is separated and purified by column chromatography to obtain the target compound after extraction and drying.

In the technical solution of the present invention, dimethyl sulfoxide is used as a diversified reaction unit, and the following reaction intermediates will exist during the reaction process, and these intermediates can also react in the same way to obtain the target product, a chromanone compound containing a quaternary carbon center at the 3rd position.

In the technical solution of the present invention, DMSO is used as both a diversified reaction unit and a reaction solvent, and the amount used is excessive, which is within the scope that can be understood by those skilled in the art.

In this application, the term "alkyl" generally refers to a straight or branched chain consisting only of carbon and hydrogen atoms, containing no unsaturation, having 1 to 8 carbon atoms and connected to the remainder of the molecule by a single bond. Hydrocarbon chain radicals such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl and 1,1-dimethylethyl (tert-butyl). The term "(C _1-6 )alkyl" refers to an alkyl group as defined above having up to 6 carbon atoms.

As used herein, the term "alkenyl" generally refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and may be straight or branched having from about 2 to about 10 carbon atoms, such as vinyl, 1-propenyl , 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl. The term "( _C2-6 )alkenyl" refers to an alkenyl group as defined above having up to 6 carbon atoms.

In this application, the term "alkynyl" generally refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond and having from 2 to 12 carbon atoms (currently preferred is a radical having from 2 to 10 carbon atoms). groups), such as ethynyl, propynyl and butynyl. The term "( _C2-6 )alkynyl" refers to an alkynyl group as defined above having up to 6 carbon atoms.

In this application, the term "alkoxy" generally refers to an alkyl, cycloalkyl, cycloalkylalkyl group connected to the remainder of the molecule via an oxygen bond as defined above. The term "substituted alkoxy" refers to an alkoxy group in which the alkyl group is substituted (i.e., -O-(substituted alkyl)), where the term "substituted alkyl" is the same as above for " "Alkyl" is defined the same way. For example, "alkoxy" refers to the group -O-alkyl, including 1 to 8 carbon atoms in straight chain, branched chain, cyclic configurations, and combinations thereof connected to the parent structure through oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy and cyclohexyloxy.

In this application, the term "halogen" refers to fluorine, chlorine, bromine, iodine, astatine.

In this application, the term "haloalkyl" refers to an alkyl group substituted by halogen.

The advantages and positive effects achieved by the present invention are:

1. The present invention provides a new synthesis method that directly activates dimethyl sulfoxide with acetic acid under metal-free catalytic conditions and provides three different synthesis units to participate in the reaction to obtain a chromanone compound containing a quaternary carbon center at the 3-position. .

2. The present invention uses o-hydroxyacetophenones that are easily available as raw materials, and uses dimethyl sulfoxide and acetic acid as mixed solvents to react in one pot to directly obtain chromanone substances containing quaternary carbon centers at the 3-position. The operation is simple. The substrate has a wide range of applications.

Description of drawings

Figure 1a-Figure 1b are hydrogen and carbon spectra of target compound 2a in Example 1 of the present invention;

Figure 2a-Figure 2b are the hydrogen spectrum and carbon spectrum of the target compound 2b in Example 2 of the present invention;

Figure 3a-Figure 3b are the hydrogen spectrum and carbon spectrum of the target compound 2c in Example 3 of the present invention;

4a-4b are hydrogen and carbon spectra of the target compound 2d in Example 4 of the present invention.

Detailed ways

The present invention will be described in detail below through specific examples, but these examples do not limit the scope of the present invention in any way, nor do they limit the protection scope of the present invention thereto. All technologies implemented based on the above contents of the present invention belong to the scope of the present invention.

Example 1 Preparation of target compound 2a compound

The reaction equation is as follows:

1a (0.2mmol, 24μL), sodium acetate (0.16mmol, 13.1mg), morpholine (0.2mmol, 18.0μL) dissolved in dimethyl sulfoxide and acetic acid (2.0mL/0.35mL) solvent were added to the reaction tube at once, stirred at 140 degrees for 30 hours under air atmosphere, then 10mL saturated sodium carbonate was added, and the organic matter was extracted three times with ethyl acetate, the organic phases were combined, dried over sodium sulfate, filtered and dried, and the initial product was purified by column chromatography (silica gel 200-300 mesh), and finally a light yellow liquid compound 2a (32.9mg, yield 69%) was obtained. The structural confirmation results of the compound are as follows:

¹ H NMR (600MHz, CDCl ₃ ) δ7.87 (dd, J=1.2, 7.8Hz, 1H), 7.49 ( td , J=1.2, 7.2Hz, 1H), 7.03 (t, J=7.2Hz, 1H) , 6.97 (d, J = 8.4Hz, 1H), 4.57 (d, J = 12.0Hz, 1H), 4.37 (d, J = 12.0Hz, 1H), 3.91 (d, J = 12.0Hz, 1H), 3.75 (d, J=12.0Hz, 1H), 2.89 (d, J=13.8Hz, 1H), 2.84 (d, J=13.8Hz, 1H), 2.65 ( br , 1H), 2.17 (s, 3H); ¹³ C NMR (150MHz, CDCl ₃ ) δ196.3, 161.4, 136.6, 127.7, 121.9, 119.9, 118.0, 70.6, 62.8, 51.0, 35.1, 18.1; HRMS (EsI) m/z [M+H ⁺ ]calcd for C ₁₂ H ₁₅ O ₃ S 239.0742, found 239.0745.

The compound synthesized after structural identification was indeed the target compound shown in 2a.

Example 2 Preparation of target compound 2b compound

The reaction equation is as follows:

Add 1b (0.2mmol, 30.8mg), sodium acetate (0.16mmol, 13.1mg), morpholine (0.2mmol, 18.0μL) dissolved in dimethyl sulfoxide and acetic acid (2.0mL/0.35mL) into the reaction tube at one time , stir for 20 hours at 140 degrees under air atmosphere, then add 10 mL saturated sodium carbonate, extract the organic matter three times with ethyl acetate, combine the organic phases, dry over sodium sulfate, filter and spin dry. The initial product is purified by column chromatography (silica gel 200 -300 mesh), finally obtained light yellow liquid compound 2b (32.3 mg, yield 63%). The structure confirmation results of this compound are as follows:

R _f =0.25 (petrolcum ether/ EtOAc 5/1); ¹ H NMR (600MHz, CDCl ₃ ) δ7.52 (dd, J = 3.0, 7.8Hz, 1H), 7.24-7.20 (m, 1H), 6.97 ( dd, J=3.6, 9.0Hz, 1H), 4.57 (d, J=11.4Hz, 1H), 4.39 (d, J=11.4Hz, 1H), 3.93 (dd, J=6.0, 11.4Hz, 1H), 3.75 (d, J=11.4Hz, 1H), 2.87 (d, J=13.8Hz, 1H), 2.84 (d, J=13.8Hz, 1H), 2.55 ( br , 1H), 2.17 (s, 3H); ¹³ C NMR (150MHz, CDCl ₃ ) δ 195.4, 157.6 (d, J=1.5Hz), 157.5 (d, J=241.5Hz), 124.1 (d, J=24.0Hz), 120.4 (d, J=6.0 Hz), 119.8 (d, J=7.5Hz), 112.5 (d, J=22.5Hz), 70.9, 62.7, 51.1, 35.0, 18.2; HRMS (ESI) m/z [M+H ⁺ ]calcd for C ₁₂ H ₁₄ FO ₃ S 257.0648, found 257.0645.

The compound synthesized after structural identification was indeed the target compound shown in 2b.

Example 3 Preparation of target compound 2c compound

The reaction equation is as follows:

In the reaction tube, add 1c (0.2mmol, 45.8mg), sodium acetate (0.16mmol, 13.1mg), morpholine (0.2mmol, 18.0μL) dissolved in dimethyl sulfoxide and acetic acid (2.0mL/0.35mL) solvent , stir for 30 hours at 140 degrees under air atmosphere, then add 10 mL saturated sodium carbonate, extract the organic matter three times with ethyl acetate, combine the organic phases, dry over sodium sulfate, filter and spin dry. The initial product is purified by column chromatography (silica gel 200 -300 mesh), finally obtained light yellow liquid compound 2c (45.0 mg, yield 68%). The structure confirmation results of this compound are as follows:

R _f =0.24 (petroleum ether/ EtOAc 5/1); ¹ H NMR (600 MHz, CDCl ₃ ) δ7.64 (s, 1H), 7.59 (s, 1H), 4.68 (d, J=12.0 Hz, 1H), 4.46 (d, J=12.0 Hz, 1H), 3.94 (d, J=10.2 Hz, 1H), 3.75 (d, J=11.4 Hz, 1H), 2.88 (d, J=13.8 Hz, 1H), 2.84 (d, J=13.8 Hz, 1H), 2.44 ( br , 1H), 2.30 (s, 3H), 2.18 (s, 3H); ¹³ C NMR (150 MHz, CDCl ₃ )δ195.5, 155.8, 140.6, 132.5, 126.9, 120.8, 111.3, 71.3, 62.8, 51.0, 35.1, 20.3, 18.2; HRMS (ESI) m/z [M+H ⁺ ] calcd for C ₁₃ H ₁₆ BrO ₃ S 331.0004, found 331.0006.

The compound synthesized after structural identification was indeed the target compound shown in 2c.

Example 4 Preparation of target compound 2d

The reaction equation is as follows:

Add 1d (0.2mmol, 38.0mg), sodium acetate (0.16mmol, 13.1mg), morpholine (0.2mmol, 18.0μL) dissolved in dimethyl sulfoxide and acetic acid (2.0mL/0.35mL) solvent into the reaction tube at a time , stir for 30 hours at 140 degrees under air atmosphere, then add 10 mL of saturated sodium carbonate, extract the organic matter three times with ethyl acetate, combine the organic phases, dry over sodium sulfate, filter and spin dry. The initial product is purified by column chromatography (silica gel 200 -300 mesh), finally obtained light yellow liquid compound 2d (43.3 mg, yield 74%). The structure confirmation results of this compound are as follows:

R _f =0.27 (petroleum ether/ EtOAc 5/1); ¹ H NMR (600MHz, CDCl ₃ ) δ7.57 (s, 1H), 6.68 (s, 1H), 4.51 (d, J = 11.4Hz, 1H) , 4.30 (d, J = 11.4Hz, 1H), 3.89 (d, J = 11.4Hz, 1H), 3.74 (d, J = 11.4Hz, 1H), 2.89 (d, J = 13.8Hz, 1H), 2.84 (d, J=13.8Hz, 1H), 2.77-2.72 (m, 4H), 2.69 ( br , 1H), 2.18 (s, 3H), 1.77 (m, 4H); ¹³ C NMR (150MHz, CDCl ₃ ) δ196.5, 159.1, 147.9, 131.4, 127.5, 117.9, 117.3, 70.5, 62.9, 50.9, 35.2, 30.3, 28.6, 23.2, 22.7, 18.1; HRMS(ESI)m/z[M+H ⁺ ]calcd for C ₁₆ H ₂₁ O ₃ S 293.1211, found 293.1214.

The compound synthesized after structural identification was indeed the target compound shown in 2d.

Although the embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various substitutions, changes and modifications are possible without departing from the spirit and scope of the present invention and the appended claims. , the scope of the present invention is not limited to the contents disclosed in the embodiments.

Claims (4)

1. A preparation method for a quaternary carbon center-containing chromanone compound, which is characterized in that using o-hydroxyacetophenones compounds shown in formula 1 as raw materials, under the action of sodium acetate and additives, dimethyl sulfoxide and The acid is a mixed solvent and heated in a one-pot method to obtain a chromanone compound containing a quaternary carbon center with the structure shown in Formula 2, Where, R represents hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, nitro, halogen, C ₁ -C ₆ alkoxy, cyano, amino, sulfonyl Acid group, halogenated C ₁ -C ₆ alkyl group, C ₆ -C ₁₀ aryl group or 5-10 membered heteroaryl group; The acid is a common protonic acid, selected from formic acid, acetic acid, propionic acid, butyric acid, hydrochloric acid, and phosphoric acid; The additive is selected from tetrahydropyrrole, morpholine, and hexahydropiperidine; n represents an integer of 0, 1, 2, 3 or 4. 2. The method according to claim 1, characterized in that the molar ratio of the reactants of the o-hydroxyacetophenone compound Formula 1 and dimethyl sulfoxide is 1:3. 3. The method according to claim 1, characterized in that the reaction temperature is 110-140 degrees and the reaction time is 10-30 hours. 4. The method according to claim 1, characterized in that the specific steps of the reaction are: Dissolve the o-hydroxyacetophenone compound shown in Formula 1 in dimethyl sulfoxide, then add sodium acetate, acid and additives, and react under heating conditions. After the reaction is complete, remove the solvent and additives in the reaction solution, and use organic The target product is extracted with a solvent, the organic phases are combined, dried, and rotary evaporated under reduced pressure to obtain a crude product, which is then chromatographed on silica gel to obtain a chromanone compound containing a quaternary carbon center with the structure of Formula 2.