CN116143598A - A palladium-catalyzed carbonylation Suzuki reaction for the synthesis of ɑ, β-unsaturated ketones - Google Patents

Abstract

The invention discloses a palladium-catalyzed carbonylation Suzuki reaction method for synthesizing ɑ, β-unsaturated ketones, belonging to the technical field of catalytic synthesis. In the method, in a solution system containing alkaline substances, organic acids and palladium catalysts, aryl halides, alkenyl boronic acids and carbon monoxide undergo coupling reactions to obtain α,β-unsaturated ketones. This method has many advantages: no need for additional ligands and good activity, high catalytic activity can be obtained by using sub-scaled bases and acids, the reaction can be carried out at normal temperature and pressure, and the selectivity is high. The functional group has good compatibility and the substrate has a wide range of application, and the reaction medium is green and can be recycled.

Description

A method for synthesizing α,β-unsaturated ketones by palladium-catalyzed carbonylation Suzuki reaction

Technical Field

The invention relates to a method for synthesizing an α,β-unsaturated ketone, and in particular to a method for directly synthesizing an α,β-unsaturated ketone by a three-component coupling reaction of an aryl halide, an alkenyl boronic acid and carbon monoxide catalyzed by ligand-free palladium, and belongs to the technical field of catalytic synthesis of fine chemicals.

Background Art

et al.,Coord.Chem.Rev.2005,249(21-22),2308-2322；Matthias Belleretal.,J.Am.Chem.Soc.2010,132(41),14596–14602)公开了Heck反应来羰基化合成ɑ,β-不饱和酮，然而该类方法合成的ɑ,β-不饱和酮局限于1,3-二取代丙烯酮结构。文献(Geng,H.-Q.；Wang,L.-C.；Hou,C.-Y.；Wu,X.-F.Org.Lett.2020,22,1160)公开了苯丙烯和碘苯及一氧化碳作为底物原料，在PdCl₂和PPh₃作为催化体系，以NEt₃作为碱，HCO₂H作为还原剂，在DMF溶液体系中反应，得到了两种烯酮产品，但是其目标产物收率较低，且催化剂需要使用配体，且反应需要在加热至80℃反应，能耗高。ɑ,β-unsaturated ketones are not only organic synthetic intermediates with high added value, widely used in the synthesis of medicines, pesticides, dyes and fragrances, but also have a wide range of biological activities. The classic method for synthesizing ɑ,β-unsaturated ketones is Claisen-Schmidt condensation. However, this method requires a strong base, and the substrate is a compound containing a carbonyl group, resulting in a lack of diversity in the synthesis of ɑ,β-unsaturated ketones. The transition metal-catalyzed carbonylation method solves these problems well: high activity without the need for a strong base; good functional group compatibility; the carbonyl source is cheap, readily available and atom-economical carbon monoxide. Reference (Józef J.

et al., Coord. Chem. Rev. 2005, 249 (21-22), 2308-2322; Matthias Beller et al., J. Am. Chem. Soc. 2010, 132 (41), 14596–14602) disclosed the Heck reaction for carbonylation synthesis of ɑ, β-unsaturated ketones. However, the ɑ, β-unsaturated ketones synthesized by this method are limited to 1,3-disubstituted propenone structures. The literature (Geng, H.-Q.; Wang, L.-C.; Hou, C.-Y.; Wu, X.-F. Org. Lett. 2020, 22, 1160) discloses that styrene, iodobenzene and carbon monoxide are used as substrate raw materials, PdCl ₂ and PPh ₃ are used as catalyst systems, NEt ₃ is used as base, HCO ₂ H is used as reducing agent, and two enone products are obtained in a DMF solution system. However, the yield of the target product is low, the catalyst requires the use of a ligand, and the reaction needs to be heated to 80°C, which has high energy consumption.

Summary of the invention

In view of the technical problems that the methods for synthesizing ɑ,β-unsaturated ketones in the prior art require strong bases, the synthesis method is single, and the types of synthesized ɑ,β-unsaturated ketones are single and narrow, the purpose of the present invention is to provide a method for synthesizing ɑ,β-unsaturated ketones by coupling reaction of aromatic halides, alkenylboronic acid and carbon monoxide using palladium catalysts. The method has significant advantages: sub-amounts of weak bases can make the reaction proceed smoothly, and the synthesis of ɑ,β-unsaturated ketones is diverse; the reaction can be carried out at room temperature and pressure with high selectivity, the reaction does not require a ligand and has good activity, the substrate source is wide and stable, the substrate functional group compatibility is good and the substrate has a wide range of application, the reaction medium is green and can be recycled, etc.

In order to achieve the above technical purpose, the present invention provides a method for synthesizing α,β-unsaturated ketones by palladium-catalyzed carbonylation Suzuki reaction, wherein the method comprises the following steps: in a solution system containing an alkaline substance, an organic acid and a palladium catalyst, an aryl halide, an alkenyl boronic acid and carbon monoxide undergo a coupling reaction to obtain an α,β-unsaturated ketone;

The aryl halide has a structure of Formula 1:

ArX

Formula 1

The alkenyl boronic acid has a structure of Formula 2:

The α,β-unsaturated ketone has a structure of Formula 3:

in,

X is bromine or iodine;

Ar is a substituted or unsubstituted phenyl, naphthyl, anthracenyl, phenanthrenyl, pyrenyl or aromatic heterocyclic group; when Ar is a substituted phenyl, naphthyl, anthracenyl, phenanthrenyl, pyrenyl or aromatic heterocyclic group, the substituent contained therein is at least one of a halogen substituent, a C ₁ to C ₁₀ alkyl group, a phenyl group, a trifluoromethyl group, a carboxyl group, a C ₂ to C ₁₆ ester group, a nitro group, a cyano group, and a C ₁ to C ₁₀ alkoxy group;

_R1 and _R2 are independently selected from hydrogen, or independently selected from substituted or unsubstituted phenyl, naphthyl, anthracenyl, phenanthryl or pyrenyl, or, _R1 and _R2 constitute a _C5 - _C8 closed aliphatic ring, and when _R1 and _R2 are selected from substituted phenyl, naphthyl, anthracenyl, phenanthryl or pyrenyl, the substituent contained therein is at least one of a halogen substituent, a _C1 - _C10 alkyl, a phenyl, a nitro, a cyano, and a _C1 - _C10 alkoxy.

In the α,β-unsaturated ketone of the present invention, Ar is a group introduced by an aromatic halide, and its selection range is relatively wide, mainly substituted or unsubstituted phenyl, naphthyl, anthracenyl, phenanthryl, pyrenyl or aromatic heterocyclic group, and these substituents can obtain a higher yield of the target product. Ar can be a phenyl or condensed ring substituent, and the condensed ring substituent is commonly naphthyl, anthracenyl, phenanthryl or pyrenyl. Ar can also be an aromatic heterocyclic group, which is mainly an aromatic heterocyclic group containing one or more heteroatoms of nitrogen, oxygen or sulfur, and the aromatic heterocyclic group can be a five-membered ring or a six-membered ring, such as thienyl, pyridyl, isoxazolyl, etc. Ar can also be a group derived from phenyl, naphthyl, anthracenyl, phenanthrenyl, pyrenyl or aromatic heterocyclic group, mainly containing common substituents on the aryl or aromatic heterocyclic group, and these substituents can be at least one of halogen substituents, C ₁ ~ C ₁₀ alkyl, phenyl, trifluoromethyl, carboxyl, C ₂ ~ C ₁₆ ester group, nitro, cyano, C ₁ ~ C ₁₀ alkoxyl group. The position of the substituent is not limited, and the number of the substituent is not limited, but generally 1 to 2 substituents are common. When the substituent is a halogen substituent, common halogen substituents such as fluorine, chlorine, and bromine can be selected. When the substituent is a C ₁ ~ C ₁₀ alkyl, it can be a straight-chain alkyl or a branched alkyl. When the number of carbon atoms exceeds 3, the alkyl can also be a cycloalkyl, such as methyl, isobutyl, cyclohexyl, etc.; when the substituent is a C ₂ ~ C ₁₆ ester group, the ester group can contain C ₁ ~ C ₁₅ Saturated aliphatic hydrocarbons or unsaturated aliphatic hydrocarbons may also contain other common organic groups, such as hydroxyl groups, carbonyl groups, etc., specifically methoxycarbonyl groups, etc.; when the substituent is a C ₁ ~C ₁₀ alkoxy group, it may be methoxy, ethoxy, isobutoxy, etc.

In the α,β-unsaturated ketone of the present invention, _R1 and _R2 are groups introduced by alkenyl boronic acid, _R1 and _R2 are substituents at positions 1 and 2 on the alkenyl, _R1 and _R2 are independently selected from hydrogen, or independently selected from substituted or unsubstituted phenyl, naphthyl, anthracenyl, phenanthryl or pyrenyl, or _R1 and _R2 form a closed aliphatic ring of _C5 to _C8 . _R1 and _R2 can be selected as hydrogen or other substituent groups at the same time, or one can be selected from hydrogen and the other can be selected from other substituent groups, and the other substituent groups can be selected from substituted or unsubstituted phenyl, naphthyl, anthracenyl, phenanthryl or pyrenyl. In a special case, _R1 and _R2 can be closed aliphatic rings, the carbon number of the aliphatic rings is generally 5 to 8, and the aliphatic rings can be saturated aliphatic rings or unsaturated aliphatic rings. When _R1 or _R2 is selected from substituted phenyl, naphthyl, anthracenyl, phenanthrenyl or pyrene, the substituent contained therein is at least one of a halogen substituent, a _C1 - _C10 alkyl, a phenyl, a nitro, a cyano, and a _C1 - _C10 alkoxy group; the position of the substituent is not limited, and the number of the substituent is not limited, but generally 1-2 substituents are common. When the substituent is a halogen substituent, common halogen substituents such as fluorine, chlorine, and bromine can be selected. When the substituent is a _C1 - _C10 alkyl, it can be a straight-chain alkyl or a branched alkyl. When the number of carbon atoms exceeds 3, the alkyl can also be a cycloalkyl, such as a methyl, isobutyl, cyclohexyl, etc.; when the substituent is a _C1 - _C10 alkoxy, it can be a methoxy, ethoxy, isobutyloxy, etc.

As a preferred embodiment, the alkaline substance includes at least one of lithium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, sodium acetate, potassium acetate, potassium pivalate, sodium pivalate, potassium phosphate, potassium hydrogen phosphate, sodium phosphate, sodium hydrogen phosphate, disodium hydrogen phosphate, potassium fluoride, tetrabutylammonium fluoride, tetrabutylammonium acetate, triethylamine, and diisopropylethylamine. The preferred alkaline substance is mainly used to activate alkenyl boronic acid to improve the conversion efficiency of alkenyl boronic acid. More preferred alkaline substances are sodium carbonate and potassium phosphate.

As a preferred embodiment, the organic acid includes at least one of formic acid, acetic acid, propionic acid, butyric acid, pivalic acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, and trifluoroacetic acid. The main function of the organic acid is to inhibit the non-carbonylation process to reduce the occurrence of side reactions and improve the selectivity of the target product. The more preferred organic acid is pivalic acid. Benzoic acid, p-toluenesulfonic acid

As a preferred solution, the palladium catalyst includes at least one of palladium powder, palladium carbon, palladium nanoparticles, palladium acetate, palladium chloride, dibenzonitrile palladium chloride, tris(dibenzylideneacetone) dipalladium, diacetonitrile palladium chloride, and sodium tetrachloropalladate.

As a preferred embodiment, the molar ratio of aryl halide, alkenyl boronic acid, alkaline substance, organic acid and palladium catalyst is 1: (1-2): (0.1-10): (0.1-10): (0.005-0.1). More preferably, the molar ratio of aryl halide, alkenyl boronic acid, alkaline substance, organic acid and palladium catalyst is 1: (1.2-1.5): (0.15-1): (0.15-1): (0.01-0.08).

As a preferred solution, the pressure of the carbon monoxide is normal pressure.

As a preferred solution, the solution system uses oligomeric polyethylene glycol and/or water solvent as solvent. The molecular weight of oligomeric polyethylene glycol is 100 to 10000. The amount of solvent is measured at a weight ratio of aryl halide to solvent of 1: (5 to 1000). The most preferred solvent is oligomeric polyethylene glycol, or an aqueous solution of oligomeric polyethylene glycol. Further preferably, the mass percentage concentration of oligomeric polyethylene glycol is not less than 0.1%. The presence of oligomeric polyethylene glycol can significantly improve the activity of palladium catalysts in catalyzing carbonylation reactions. The molecular weight of oligomeric polyethylene glycol is more preferably 200 to 1000, more preferably 200 to 600.

As a preferred solution, the coupling reaction conditions are: temperature of 20 to 100° C. and time of 0.5 to 60 hours.

The specific reaction formula for synthesizing α,β-unsaturated ketone by coupling reaction of aryl halide, alkenyl boronic acid and carbon monoxide is as follows:

The reaction mechanism of the present invention for synthesizing α,β-unsaturated ketones through coupling reaction of aryl halides, alkenyl boronic acid and carbon monoxide is as follows: first, zero-valent palladium (high-valent palladium can be reduced to zero-valent palladium by alcohol) can undergo oxidative addition with aryl halides to form an aryl palladium intermediate, which can undergo insertion reaction with carbon monoxide CO to form an aromatic acyl palladium intermediate; after being activated by alkali and solvent, alkenyl boronic acid can undergo metal transfer reaction with the aromatic acyl palladium intermediate to form an important acyl palladium alkenyl intermediate, which is then reduced and eliminated to obtain the target carbonylation product, and a zero-valent palladium catalyst is formed to complete a catalytic cycle process.

Compared with the prior art, the technical solution of the present invention has the following beneficial technical effects:

(1) The method for synthesizing α,β-unsaturated ketones provided by the present invention has the unique advantages of not requiring a ligand and reacting at normal pressure; the reaction does not require a ligand and has good activity; the reaction is carried out at normal pressure and has high selectivity; a weak sub-stoichiometric base can make the reaction proceed smoothly; and it is suitable for the late carbonylation of complex molecules, which has important application value in the fields of medicine and biochemistry.

(2) The method for synthesizing ɑ,β-unsaturated ketones provided by the present invention has a wide range of substrate sources, is stable and inexpensive, is simple to operate, and can directly obtain ɑ,β-unsaturated ketones with diverse structures in one step. Under optimized reaction conditions, the separation yield of the target product is as high as 95%. The method is a general, efficient, economical and environmentally friendly method for synthesizing ɑ,β-unsaturated ketones;

(3) In the synthesis method of α,β-unsaturated ketone provided by the present invention, the use of oligomeric polyethylene glycol and its aqueous solution as a solvent can significantly improve the activity of palladium-catalyzed carbonylation. At the same time, the coordinated regulation of base and acid can suppress the problem of non-carbonylation side reactions, thereby ensuring the advantages of high selectivity of the reaction, good functional group compatibility and a wide range of applications.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is the H NMR spectrum of compound 1.

Figure 2 is the NMR carbon spectrum of compound 1.

FIG3 is the H NMR spectrum of compound 16.

FIG4 is the NMR carbon spectrum of compound 16.

DETAILED DESCRIPTION

The content of the present invention is further described in detail below in conjunction with specific embodiments, but the protection scope of the claims of the technical solution of the present invention is not limited by the specific embodiments.

In order to further explain the technical means and effects adopted by the present invention to achieve the predetermined invention purpose, the specific implementation methods, features and effects of the technical solution proposed in the present invention are described in detail as follows.

In the following examples, if there is no special explanation, the reaction raw materials are conventional commercially available raw materials, and the detection means are conventional detection means.

Preferred example of conditions:

The following experiments use the reaction between 1a and 2a to examine the effects of different palladium catalysts, alkaline substances, organic carboxylic acids, polyethylene glycol, etc. on the reaction.

Palladium catalyst (0.002mmol), alkaline substance (0.15mmol), 1a (0.1mmol), 2a (0.12mmol), organic carboxylic acid (0.05mmol) and polyethylene glycol (2mL) were added to a 10mL reaction bottle in sequence, and carbon monoxide was introduced at an atmospheric pressure. The reaction mixture was reacted at 25°C for 3h. After the reaction was completed, 10mL of saturated brine was added, and the mixture was extracted with ether (10mL×3). The organic phases were combined, the solvent was evaporated under reduced pressure, and then separated by column chromatography.

^b Na ₂ CO ₃ (0.5equiv.). ^c Na ₂ CO ₃ (0.25equiv.). ^d PivOH (1equiv.)

Experimental groups 1 to 4 in the above table investigated the effects of different organic acids on the coupling reaction between aromatic halides, alkenyl boronic acids and carbon monoxide. The experiments showed that if no organic acid was added, although the conversion rate of the raw materials was high, the selectivity was significantly poor. Adding an appropriate amount of organic acid could significantly inhibit the occurrence of side reactions. For example, PivOH, C ₆ H ₅ CO ₂ H, TsOH ^. H ₂ O, etc. all had similar effects. However, when PivOH was used, the selectivity of the target product α,β-unsaturated ketone was significantly better than that of other organic acids.

Experimental groups 2, 5, 6 and 23 in the above table investigated the effects of different palladium catalysts on the coupling reaction between aromatic halides, alkenyl boronic acids and carbon monoxide. The experiments showed that without the addition of palladium catalysts, the reaction could not proceed smoothly, while different palladium catalysts did not have a significant effect on the reaction. Palladium salts such as Pd(OAc) ₂ , Pd/C, and Pd ₂ (dba) ₃ , metallic palladium or palladium complexes can promote the smooth progress of the reaction. The yield of the target product ɑ,β-unsaturated ketone using Pd(OAc) ₂ is slightly higher than that of other palladium catalysts.

Experimental groups 2, 7 to 15 and 24 in the above table investigated the effects of different alkaline substances on the coupling reaction between aromatic halides, alkenyl boronic acids and carbon monoxide. The experiments showed that if no alkaline substance is used, basically no target product can be obtained. When alkaline substances are added, most alkaline substances can make the reaction proceed smoothly. However, different alkaline substances have a relatively large effect on the yield and selectivity of the target product. For example, the selectivity of Na ₃ PO ₄ , K ₂ CO ₃ , Et ₃ N, NaOAc, etc. is relatively poor, while the selectivity and yield of KF, NaHCO ₃ , Li ₂ CO _3, etc. are relatively poor. When sodium carbonate and potassium phosphate are selected, the yield and selectivity of the target product are relatively high.

Experimental groups 2 and 16-18 in the above table investigated the effects of different amounts of alkaline substances and organic acids on the coupling reaction between aromatic halides, alkenyl boronic acids and carbon monoxide. The experiments showed that as the amount of alkaline substances used increased, the yield and selectivity of the target product reached the highest values, and the addition of an appropriate amount of acid could also increase the yield of the target product.

Experimental groups 2 and 19 to 22 in the above table investigated the effects of different solvents on the coupling reaction between aromatic halides, alkenyl boronic acids and carbon monoxide. The experiments showed that in most organic solvents, the reaction could not proceed smoothly or the yield of the target product was very low. However, when polyethylene glycol was used, the yield of the target product could be significantly increased. In particular, the smaller the molecular weight of the oligomeric polyethylene glycol used, the more conducive it was to increasing the yield of the target product.

The following Examples 1 to 21 further illustrate the reaction effects of different substrates under optimized reaction conditions.

Example 1

Compound 1: Palladium acetate (0.01mmol), lithium carbonate (0.25mmol), 1a (0.5mmol), 2a (0.6mmol), acetic acid (0.25mmol) and polyethylene glycol-400 (2.0g) were added to a 25mL reaction bottle in sequence, and carbon monoxide was introduced at an atmospheric pressure. The reaction mixture was reacted at 25°C for 3h. After the reaction was completed, 10mL of saturated brine was added, and it was extracted with ether (10mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed to obtain a yield of 91%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.91 (d, J = 8.8Hz, 2H), 7.84 (d, J = 16.0Hz, 1H), 7.67-7.65 (m, 4H), 7.50 (d, J = 16.0Hz, 1H), 7.45-7.44ppm (m, 3H); ¹³ C NMR (100MHz, CDCl ₃ )δ189.3,145.4,136.9,134.6,131.9,130.7,130.0,129.0,128.5,127.9,121.4ppm.

Example 2

Compound 2: Palladium acetate (0.01mmol), sodium carbonate (0.25mmol), 1b (0.5mmol), 2a (0.6mmol), pivalic acid (0.25mmol) and polyethylene glycol-400 (2.0g) were added to a 25mL reaction bottle in sequence, and carbon monoxide was introduced at an atmospheric pressure. The reaction mixture was reacted at 25°C for 3h. After the reaction was completed, 10mL of saturated brine was added, and it was extracted with ether (10mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was used to separate the yield of 89%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.99 (d, J = 8.8Hz, 2H), 7.84 (d, J = 15.6Hz, 1H), 7.67-7.65 (m, 2H), 7.51 (d, J = 15.6Hz, 1H), 7.49 (d, J = 8.8Hz, 2H), 7.46-7.43ppm (m, 3H ); ¹³ C NMR (100MHz, CDCl ₃ ) δ189.1,145.3,139.2,136.5,134.5,130.7,129.9,129.0,128.9,128.5,121.5ppm

Example 3

Compound 3: Palladium acetate (0.01mmol), sodium bicarbonate (0.5mmol), 1c (0.5mmol), 2a (0.6mmol), pivalic acid (0.25mmol) and polyethylene glycol-400 (2.0g) were added to a 25mL reaction bottle in sequence, and carbon monoxide was introduced at an atmospheric pressure. The reaction mixture was reacted at 25°C for 1h. After the reaction was completed, 10mL of saturated brine was added, and it was extracted with ether (10mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed to obtain a yield of 94%. ¹ H NMR (400MHz, CDCl ₃ ) δ8.37 (d, J = 8.8Hz, 2H), 8.17 (d, J = 8.8Hz, 2H), 7.88 (d, J = 15.6Hz, 1H), 7.69-7.67 (m, 2H), 7.51 (d, J = 15.6Hz, 1H), 7.48-7.45ppm (m, 3H ); ¹³ C NMR (100MHz, CDCl ₃ ) δ 189.0, 150.0, 146.8, 143.0, 134.3, 131.2, 129.4, 129.1, 128.7, 123.8, 121.2ppm.

Example 4

Compound 4: Dibenzonitrile palladium chloride (0.01mmol), potassium carbonate (0.25mmol), 1d (0.5mmol), 2a (0.5mmol), methanesulfonic acid (0.25mmol) and polyethylene glycol-400 (2.0g) were added to a 25mL reaction bottle in sequence, and carbon monoxide at an atmospheric pressure was introduced. The reaction mixture was reacted at 25°C for 6h. After the reaction was completed, 10mL of saturated brine was added, and it was extracted with ether (10mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was used to separate the yield of 80%.

Example 5

Compound 5: Palladium chloride (0.01mmol), cesium carbonate (0.5mmol), 1e (0.5mmol), 2a (0.6mmol), butyric acid (0.25mmol) and polyethylene glycol-200 (2.0g) were added to a 25mL reaction bottle in sequence, and carbon monoxide was introduced at an atmospheric pressure. The reaction mixture was reacted at 25°C for 3h. After the reaction was completed, 10mL of saturated brine was added, and ether was extracted (10mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed to obtain a yield of 66%.

Example 6

Compound 6: Palladium nanoparticles (0.01mmol), sodium phosphate (0.25mmol), 1f (0.5mmol), 2a (0.6mmol), p-toluenesulfonic acid (0.25mmol) and polyethylene glycol-400 (2.0g) were added to a 25mL reaction bottle in sequence, and carbon monoxide at an atmospheric pressure was introduced. The reaction mixture was reacted at 25°C for 3h. After the reaction was completed, 10mL of saturated brine was added, and the mixture was extracted with ether (10mL×3). The organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed to obtain a yield of 91%.

Example 7

Compound 7: Palladium powder (0.01mmol), potassium bicarbonate (0.25mmol), 1g (0.5mmol), 2a (0.6mmol), benzoic acid (0.25mmol) and polyethylene glycol-400 (2.0g) were added to a 25mL reaction bottle in sequence, and carbon monoxide was introduced at an atmospheric pressure. The reaction mixture was reacted at 25°C for 3h. After the reaction was completed, 10mL of saturated brine was added, and it was extracted with ether (10mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed to obtain a yield of 82%. ¹ H NMR(400MHz,CDCl ₃ )δ8.14(d,J＝8.4Hz,2H),7.88(d,J＝15.6Hz,1H),7.76(d,J＝8.4Hz,2H),7.71-7.67(m,4H),7.62(d,J＝15.6Hz,1H),7.53-7.49(m,2H),7.48-7.41ppm(m,4H)； ¹³ C NMR(100MHz,CDCl ₃ )δ189.9,145.5,144.7,139.9,136.9,134.9,130.5,129.1,128.9,128.9,128.4,128.2,127.3,122.0ppm。

Example 8

Compound 8: Palladium/carbon (0.01mmol), sodium acetate (0.25mmol), 1h (0.5mmol), 2a (0.6mmol), benzoic acid (0.25mmol) and polyethylene glycol-400 (2.0g) were added to a 25mL reaction bottle in sequence, and carbon monoxide at an atmospheric pressure was introduced. Subsequently, hydrogen peroxide (0.5mmol) was added dropwise. The reaction mixture was reacted at 25°C for 3h. After the reaction was completed, 10mL of saturated brine was added, and the mixture was extracted with ether (10mL×3). The organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed to obtain a yield of 78%.

Example 9

Compound 9: Palladium acetate (0.01mmol), potassium acetate (0.25mmol), 1i (0.5mmol), 2a (0.6mmol), formic acid (0.25mmol) and polyethylene glycol-400 (2.0g) were added to a 5mL reaction bottle in sequence, and carbon monoxide at an atmospheric pressure was introduced. The reaction mixture was reacted at 25°C for 9h. After the reaction was completed, 10mL of saturated brine was added, and it was extracted with ether (10mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed to obtain a yield of 92%.

Example 10

Compound 10: Diacetonitrile palladium chloride (0.01mmol), potassium bicarbonate (0.25mmol), 1j (0.5mmol), 2a (0.6mmol), propionic acid (0.25mmol) and polyethylene glycol-400 (2.0g) were added to a 5mL reaction bottle in sequence, and carbon monoxide at an atmospheric pressure was introduced. The reaction mixture was reacted at 25°C for 3h. After the reaction was completed, 10mL of saturated brine was added, and it was extracted with ether (10mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed to obtain a yield of 86%.

Embodiment 11

Compound 11: Sodium tetrachloropalladate (0.01mmol), potassium pivalate (0.25mmol), 1k (0.5mmol), 2a (0.6mmol), trifluoroacetic acid (0.25mmol), polyethylene glycol-8000 (2.0g) and water (2.0g) were added to a 5mL reaction bottle in sequence, and carbon monoxide was introduced at an atmospheric pressure. The reaction mixture was reacted at 25°C for 3h. After the reaction was completed, 10mL of saturated brine was added, and it was extracted with ether (10mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed to obtain a yield of 85%.

Example 12

Compound 12: Tris(dibenzylideneacetone)dipalladium (0.01mmol), sodium pivalate (0.25mmol), 1l (0.5mmol), 2a (0.6mmol), pivalic acid (0.25mmol) and polyethylene glycol-400 (2.0g) were added to a 5mL reaction bottle in sequence, and carbon monoxide was introduced at an atmospheric pressure. The reaction mixture was reacted at 25°C for 3h. After the reaction was completed, 10mL of saturated brine was added, and the mixture was extracted with ether (10mL×3). The organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed to obtain a yield of 87%.

Example 13

Compound 13: Palladium acetate (0.01mmol), potassium phosphate (0.15mmol), 1m (0.5mmol), 2a (0.6mmol), pivalic acid (0.25mmol) and polyethylene glycol-400 (2.0g) were added to a 5mL reaction bottle in sequence, and carbon monoxide was introduced at an atmospheric pressure. The reaction mixture was reacted at 25°C for 3h. After the reaction was completed, 10mL of saturated brine was added, and it was extracted with ether (10mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was used to separate the yield of 95%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.70 (d, J = 15.6Hz, 1H), 7.62-7.59 (m, 2H), 7.46-7.43 (m, 3H), 7.12 (d, J = 15.6Hz, 1H), 2.70 (s, 3H), 2.51ppm (s, 3H); ¹³ C NMR (100MHz, CDCl ₃ )δ185.3,173.0,159.1,144.6,134.3,130.9,129.1,128.4,124.3,117.4,13.8,12.1ppm.

Embodiment 14

Compound 14: Palladium acetate (0.01mmol), potassium hydrogen phosphate (0.15mmol), 1n (0.5mmol), 2a (0.6mmol), pivalic acid (0.25mmol) and polyethylene glycol-400 (2.0g) were added to a 5mL reaction bottle in sequence, and carbon monoxide was introduced at an atmospheric pressure. The reaction mixture was reacted at 25°C for 3h. After the reaction was completed, 10mL of saturated brine was added, and it was extracted with ether (10mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed to obtain a yield of 68%.

Embodiment 15

Compound 15: Palladium acetate (0.01mmol), sodium hydrogen phosphate (0.15mmol), 1o (0.5mmol), 2b (0.6mmol), pivalic acid (0.25mmol) and polyethylene glycol-400 (2.0g) were added to a 5mL reaction bottle in sequence, and carbon monoxide was introduced at an atmospheric pressure. The reaction mixture was reacted at 25°C for 3h. After the reaction was completed, 10mL of saturated brine was added, and it was extracted with ether (10mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed to obtain a yield of 90%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.61(d,J＝8.0Hz,2H),7.41(d,J＝8.0Hz,2H),6.58-6.43(m,1H),2.42-2.40(m,2H),2.31-2.27(m,2H),1.78-1.72(m,2H),1.72-1 .66ppm (m, 2H); ¹³ C NMR (100MHz, CDCl ₃ ) δ 196.9, 144.1, 138.6, 137.5, 136.9, 130.6, 128.3, 26.1, 23.9, 21.9, 21.6ppm.

Example 16

Compound 16: Palladium acetate (0.01mmol), disodium hydrogen phosphate (0.15mmol), 1o (0.5mmol), 2c (0.6mmol), pivalic acid (0.25mmol) and polyethylene glycol-400 (2.0g) were added to a 5mL reaction bottle in sequence, and carbon monoxide was introduced at an atmospheric pressure. The reaction mixture was reacted at 50°C for 1h. After the reaction was completed, 10mL of saturated brine was added, and it was extracted with ether (10mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed to obtain a yield of 87%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.86 (d, J = 8.4Hz, 2H), 7.43-7.41 (m, 3H), 7.40-7.38 (m, 2H), 7.38-7.36 (m, 2H), 6.09 (s, 1H), 5.67ppm (s, 1H); ¹³ C NMR (100MHz, CDCl ₃ )δ196.3,148.0,139.6,136.7,135.3,131.4,128.8,128.7,128.6,127.0,121.1ppm.

Embodiment 17

Compound 17: Palladium acetate (0.01mmol), potassium fluoride (0.15mmol), 1o (0.5mmol), 2d (0.6mmol), pivalic acid (0.25mmol) and polyethylene glycol-400 (2.0g) were added to a 5mL reaction bottle in sequence, and carbon monoxide at an atmospheric pressure was introduced. The reaction mixture was reacted at 25°C for 6h. After the reaction was completed, 10mL of saturated brine was added, and the mixture was extracted with ether (10mL×3). The organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed to obtain a yield of 88%.

Embodiment 18

Compound 18: Palladium acetate (0.01mmol), tetrabutylammonium fluoride (0.15mmol), 1o (0.5mmol), 2e (0.6mmol), pivalic acid (0.25mmol) and polyethylene glycol-400 (2.0g) were added to a 5mL reaction bottle in sequence, and carbon monoxide at an atmospheric pressure was introduced. The reaction mixture was reacted at 25°C for 3h. After the reaction was completed, 10mL of saturated brine was added, and it was extracted with ether (10mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed to obtain a yield of 90%.

Embodiment 19

Compound 19: Palladium acetate (0.01mmol), tetrabutylammonium acetate (0.15mmol), 1o (0.5mmol), 2f (0.6mmol), pivalic acid (0.25mmol) and polyethylene glycol-400 (2.0g) were added to a 5mL reaction bottle in sequence, and carbon monoxide at an atmospheric pressure was introduced. The reaction mixture was reacted at 25°C for 3h. After the reaction was completed, 10mL of saturated brine was added, and it was extracted with ether (10mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed to obtain a yield of 78%.

Embodiment 20

Compound 20: Palladium acetate (0.01mmol), triethylamine (0.15mmol), 1o (0.5mmol), 2g (0.6mmol), pivalic acid (0.25mmol) and polyethylene glycol-400 (2.0g) were added to a 55mL reaction bottle in sequence, and carbon monoxide at an atmospheric pressure was introduced. The reaction mixture was reacted at 25°C for 3h. After the reaction was completed, 10mL of saturated brine was added, and it was extracted with ether (10mL×3), the organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed to obtain a yield of 72%.

Embodiment 21

Compound 21: Palladium acetate (0.01mmol), diisopropylethylamine (0.15mmol), 1p (0.5mmol), 2a (0.6mmol), pivalic acid (0.25mmol) and polyethylene glycol-400 (2.0g) were added to a 5mL reaction bottle in sequence, and carbon monoxide was introduced at an atmospheric pressure. The reaction mixture was reacted at 25°C for 3h. After the reaction was completed, 10mL of saturated brine was added, and the mixture was extracted with ether (10mL×3). The organic phases were combined, the solvent was evaporated under reduced pressure, and then column chromatography was performed to obtain a yield of 62%.

The experimental results corresponding to the synthesis methods of specific α,β-unsaturated ketones involved in Examples 1 to 21 are listed in Table 1:

Table 1 Palladium-catalyzed carbonylation synthesis of ɑ,β-unsaturated ketones ^[a]

[a] Reaction conditions see Example; [b] Column separation yield.

The above is only a preferred embodiment of the present invention, and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment, it is not used to limit the present invention. It is not difficult for any technician familiar with this profession to understand that without departing from the scope of the technical solution of the present invention, changes or modifications can be made to obtain corresponding embodiments. For example, the substituents can be replaced, changed or modified within the scope of the present invention, and the method of the present invention can be implemented. However, any modification, modification or equivalent and equivalent changes made to the above embodiments according to the present invention without departing from the purpose of the technical solution of the present invention still fall within the scope of the technical solution of the present invention.

Claims (8)

1. A method for synthesizing alpha, beta-unsaturated ketone by palladium-catalyzed carbonylation Suzuki reaction is characterized by comprising the following steps: in a solution system containing alkaline substances, organic acid and palladium catalysts, carrying out coupling reaction on aryl halide, alkenyl boric acid and carbon monoxide to obtain alpha, beta-unsaturated ketone;

the aryl halide has the structure of formula 1:

Ar-X

1 (1)

The alkenyl boronic acid has the structure of formula 2:

the alpha, beta-unsaturated ketone has a structure of formula 3:

wherein,,

x is bromine or iodine;

ar is substituted or unsubstituted phenyl, naphthyl, anthryl, phenanthryl, pyrenyl or aromatic heterocyclic group; ar is substituted phenyl, naphthyl, anthryl, phenanthryl, pyrenyl or aromatic heterocyclic group, and the substituent contained in Ar is halogen substituent, C ₁ ～C ₁₀ Alkyl, phenyl, trifluoromethyl, carboxyl, C ₂ ～C ₁₆ Ester group, nitro group, cyano group, C ₁ ～C ₁₀ At least one of alkoxy groups;

R ₁ and R is ₂ Independently selected from hydrogen, or independently selected from substituted or unsubstituted phenyl, naphthyl, anthryl, phenanthryl or pyrenyl, or R ₁ And R is ₂ Form C ₅ ～C ₈ Is a closed aliphatic ring of R ₁ Or R is ₂ When selected from substituted phenyl, naphthyl, anthryl, phenanthryl or pyrenyl, the substituent is halogen substituent, C ₁ ～C ₁₀ Alkyl, phenyl, nitro, cyano, C ₁ ～C ₁₀ At least one of alkoxy groups.

2. The method for synthesizing alpha, beta-unsaturated ketone by palladium-catalyzed carbonylation Suzuki reaction according to claim 1, which is characterized in that: the alkaline substance comprises at least one of lithium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, sodium acetate, potassium pivalate, sodium pivalate, potassium phosphate, potassium hydrogen phosphate, sodium hydrogen phosphate, disodium hydrogen phosphate, potassium fluoride, tetrabutylammonium acetate, triethylamine and diisopropylethylamine.

3. The method for synthesizing alpha, beta-unsaturated ketone by palladium-catalyzed carbonylation Suzuki reaction according to claim 1, which is characterized in that: the organic acid comprises at least one of formic acid, acetic acid, propionic acid, butyric acid, pivalic acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid and trifluoroacetic acid.

4. The method for synthesizing alpha, beta-unsaturated ketone by palladium-catalyzed carbonylation Suzuki reaction according to claim 1, which is characterized in that: the palladium catalyst comprises at least one of palladium powder, palladium carbon, palladium nano, palladium acetate, palladium chloride, dibenzonitrile palladium chloride, tris (dibenzylideneacetone) dipalladium, diacetonitrile palladium chloride and sodium tetrachloropalladate.

5. The method for synthesizing alpha, beta-unsaturated ketone by palladium-catalyzed carbonylation Suzuki reaction according to any one of claims 1 to 4, which is characterized in that: the molar ratio of the aryl halide to the alkenyl boric acid to the alkaline substance to the organic acid to the palladium catalyst is 1 (1-2): 0.1-10: (0.005-0.1).

6. The method for synthesizing alpha, beta-unsaturated ketone by palladium-catalyzed carbonylation Suzuki reaction according to claim 1, which is characterized in that: the pressure of the carbon monoxide is normal pressure.

7. The method for synthesizing alpha, beta-unsaturated ketone by palladium-catalyzed carbonylation Suzuki reaction according to claim 1, which is characterized in that: the solution system adopts oligomeric polyethylene glycol and/or an aqueous solvent as a solvent.

8. The method for synthesizing alpha, beta-unsaturated ketone by palladium-catalyzed carbonylation Suzuki reaction according to claim 1, 2, 3, 4, 6 or 7, wherein the method comprises the following steps: the conditions of the coupling reaction are as follows: under normal pressure, the temperature is 20-100 ℃ and the time is 0.5-60 hours.

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