CN108976122A - The method for preparing 1,3- dicarbonyl compound based on metal hydride/palladium compound system - Google Patents

Abstract

The invention discloses a method for preparing a 1,3-dicarbonyl compound based on a metal hydride/palladium compound system, comprising the following steps: suspending a palladium compound and a metal hydride in a solvent under nitrogen protection, and then adding an electron-deficient alkene compound, React at 0°C-100°C for 0.3-10 hours, then add saturated ammonium chloride aqueous solution to stop the reaction, then extract, evaporate to dryness, and purify by column chromatography to obtain the product 1,3-dicarbonyl compound. The hydride and palladium compound catalysts used in the present invention are reagents that are easily obtained in the laboratory. Compared with the commonly used hydrogen hydrogenation method, the method is easier to operate, has higher safety, mild conditions and high reaction yield.

Description

Preparation of 1,3-dicarbonyl compounds based on metal hydride/palladium compound system method

technical field

The invention belongs to the technical field of organic synthesis, and specifically relates to the application of a metal hydride/palladium compound system in the Michael-Dieckmann series reaction of electron-deficient alkenes, and in particular to the preparation of 1,3-dicarbonyl compounds based on a metal hydride/palladium compound system method.

Background technique

Sodium hydride is a strong base that is often used in laboratories and industries. For a long time, there have been few reports about its use as a reducing agent. Existing technologies utilizing sodium hydride all require a large excess of sodium hydride (more than 5 equivalents), and require at least 2 equivalents of sodium iodide as a promoter.

The reduction of electron-deficient alkenes is a common chemical transformation to the corresponding saturated carbonyl compounds. This type of reaction is generally reduced by hydrogen/palladium carbon; in addition, some hydrogen negative reagents, such as [(Ph ₃ P)CuH] ₆ (Stryker reagent), R ₃ SiH, Hantzsch ester, etc. can also complete this electron-deficient Reduction of the double bond. However, these reducing conditions are either dangerous, such as explosive hydrogen gas; or the reagents are expensive, the reaction lacks atom economy, and more wastes need to be disposed of after the reaction, such as [(Ph ₃ P)CuH] ₆ ( Stryker reagent), R ₃ SiH, Hantzsch ester, etc.

Contents of the invention

The technical problem to be solved in the present invention is to provide an application of a metal hydride/palladium compound catalytic reduction system, thereby providing an electron-deficient alkene compound 1 substituted by an ortho-ester group to perform a Michael-Dieckmann series reaction to generate 1,3- Method for dicarbonyl compounds 3.

The present invention adopts following technical scheme:

The method for preparing a 1,3-dicarbonyl compound based on a metal hydride/palladium compound system comprises the following steps, under nitrogen protection, suspending the palladium compound and the metal hydride in a solvent, then adding an electron-deficient alkene compound, at 0° C. to React at 100°C for 0.3 to 10 hours to obtain 1,3-dicarbonyl compound.

The technical means of the present invention to realize the above-mentioned series reaction (Michael-Dieckmann) is to use metal hydride as a reducing agent, palladium and its salts as a catalyst, and an electron-deficient alkene compound as a substrate to react in a solvent to obtain a series product 1,3-dicarbonyl compounds.

In the present invention, the metal hydrides are sodium hydride, lithium hydride, potassium hydride and calcium hydride, preferably sodium hydride and lithium hydride, more preferably sodium hydride.

In the present invention, the palladium compound is palladium chloride, palladium acetate, Pd ₂ (dba) ₃ , Pd(TFA) ₂ , [(η ³ -C ₃ H ₅ )PdCl] ₂ , Pd(dppp)Cl ₂ , Pd(C ₆ H ₅ CN) ₂ Cl ₂ , Pd(OH) ₂ , preferably palladium chloride and palladium acetate, more preferably palladium chloride.

The Michael-Dieckmann series reaction of sodium hydride/palladium has the following advantages: 1) Compared with other reducing agents, the price of sodium hydride is very cheap; compared with hydrogen reduction, the safety of sodium hydride method is higher. 2) Sodium hydride has a small molecular weight and simple composition, and is used in a small amount in the reaction, so using sodium hydride as a reducing agent is an atom-economical method; except for the harmless sodium salt, no other waste is produced as a by-product. 3) Sodium hydride and palladium catalysts are commonly used reagents in laboratories and are very convenient to use. 4) Compared with the Stryker reagent, the combination of sodium hydride/palladium is much cheaper, and the palladium reagent can be recycled, so it is more suitable for laboratory and industrial applications.

In the present invention, the chemical structural formula of the electron-deficient alkene compound is as follows:

R is an aryl group, an alkyl group, an alkoxy group, an amino group or the like.

In the present invention, the molar ratio of the palladium compound, metal hydride, and electron-deficient alkenes is (0.01～1):(1-5):1, preferably, the palladium compound, metal hydrides, electron-deficient alkenes The molar ratio of the compounds is (0.05-0.15): (1-3): 1, more preferably, the molar ratio of the palladium compound, the metal hydride, and the electron-deficient alkene compound is 0.1: (1.5-2.5): 1, Most preferably, the molar ratio of the palladium compound, the metal hydride, and the electron-deficient alkene compound is 0.1:2:1.

Above-mentioned technical scheme can be expressed as follows:

Wherein R is an aryl group, an alkyl group, an alkoxy group, an amino group, etc.; M is a metal such as lithium, sodium, potassium, calcium, etc.

The conversion from compound 1 to compound 3 in the prior art can be completed step by step, for example, the double bond is first reduced by hydrogen, and then treated with alkali to obtain 3; it can also be completed by using Stryker reagent in one pot, that is, firstly remove the missing compound in 1. Electronene undergoes Michael-type conjugate reduction and Dieckmann reaction to obtain 3; among them, the step-by-step reaction is complicated to operate, the cost is high, and a lot of waste is generated. Although the one-pot series reaction is simple, the Stryker reagent is very expensive (1g>500 yuan) , so the comprehensive cost is actually higher than the footwork.

In the above technical scheme, after the reaction is completed, a saturated ammonium chloride aqueous solution is added to stop the reaction, extracted with a solvent, evaporated to dryness, and purified by column chromatography to obtain the product 1,3-dicarbonyl compound.

In the above technical solution, the solvent is DMA (N,N-dimethylacetamide), DMF, THF, DME or dioxane.

In the above technical solution, the reaction temperature is preferably 25-60° C.; the reaction time is preferably 0.3-2 hours.

The preparation of 1,3-dicarbonyl compound 3 from the electron-deficient alkene compound 1 substituted by the ortho ester group generally adopts two types of methods: one is to use hydrogen gas/palladium carbon for hydrogenation to reduce the double bond, and then Dieckmann condensation under basic conditions , in this process, the use of hydrogen is a potential dangerous factor, and improper operation will cause fire and explosion; the other is to use very expensive Stryker reagents for direct series reactions. Therefore, the present invention uses relatively safe and cheap metal hydrides for the Michael-Dieckmann tandem reaction to be of great significance; Methods.

The hydride and palladium compound catalysts used in the present invention are reagents that are easily obtained in the laboratory. Compared with the commonly used hydrogen hydrogenation method, the method is easier to operate, has higher safety, mild conditions and high reaction yield.

Detailed ways

Example 1

Under nitrogen protection, palladium chloride (5.3 mg, 0.03 mmol, 10 mol%) and sodium hydride (60% in oil, 24 mg, 0.6 mmol, 2 equiv) were suspended in DMA (1.5 mL), stirred at 25°C for 5 minutes, Add a solution of compound 1a (0.3 mmol) in DMA (0.5 mL), then react at 25°C for 2 hours, add saturated aqueous ammonium chloride solution to stop the reaction, extract with ethyl acetate, combine the extracts, dry over sodium sulfate, and rotary evaporate Evaporated to dryness and purified by column chromatography, the product 3a was obtained with a yield of >99%. The mixture of enol and keto form, enol/keto = 16/84. ¹ H NMR (400 MHz, CDCl ₃ ): δ10.37 (br, 1H, enol), 7.78 (d, J = 7.6 Hz, 1H), 7.63 (t, J = 7.2 Hz, 1H), 7.53-7.35 (m, 2H), 3.86 (s, 3H, enol), 3.79 (s, 3H, keto), 3.74 (dd, J = 8.1, 3.9 Hz, 1H , keto), 3.57 (dd, J = 17.3, 3.4 Hz, 1H, keto), 3.52 (s, 2H, enol), 3.38 (dd, J = 17.2, 8.2 Hz, 1H, keto). ¹³ C NMR (151 MHz, CDCl ₃ ): δ 199.58,169.68, 153.73, 143.33 (enol), 135.61, 135.32 (enol), 129.54 (enol), 127.97,126.97 (enol), 126.68, 124.86, 120.83, 2.3 (enol) 52.95, 51.39 (enol), 32.65 (enol), 30.40. LR-MS (ESI): m/z 191.2 [M+H]+.

Example 2

Under nitrogen protection, palladium acetate (2.7 mg, 0.015 mmol, 5 mol%) and lithium hydride (7.2 mg, 0.9 mmol, 3.0 equiv) were suspended in DMF (1.5 mL), stirred at 25°C for 5 minutes, compound 1a (0.3 mmol ) in DMF (0.5mL), react at 100°C for 0.3 hours, add saturated aqueous ammonium chloride solution to stop the reaction, extract with ethyl acetate, combine the extracts, dry with sodium sulfate, evaporate to dryness by rotary evaporation, column chromatography After purification, the product 3a was obtained in a yield of 91%.

Example 3

Under nitrogen protection, Pd ₂ (dba) ₃ (2.7 mg, 0.003 mmol, 1 mol%) and potassium hydride (30% in oil, 200 mg, 1.5 mmol, 5 equiv) were suspended in THF (1.5 mL), stirred at 25°C For 5 minutes, add a solution of compound 1a (0.3mmol) in THF (0.5 mL), then react at 0°C for 10 hours, add saturated aqueous ammonium chloride solution to stop the reaction, extract with ethyl acetate, combine the extracts, and dry over sodium sulfate , evaporated to dryness by rotary evaporation, and purified by column chromatography to obtain product 3a with a yield of 82%.

Example 4

Under nitrogen protection, Pd(TFA) ₂ (100 mg, 0.3 mmol, 100 mol%) and calcium hydride (24 mg, 0.6 mmol, 2.0 equiv) were suspended in DME (1.5 mL), stirred at 25°C for 5 minutes, and compound 1a was added (0.3 mmol) in DME (0.5 mL), then reacted at 90°C for 0.3 hours, added saturated aqueous ammonium chloride solution to stop the reaction, extracted with ethyl acetate, combined the extracts, dried over sodium sulfate, and evaporated to dryness. Purified by column chromatography, the product 3a was obtained with a yield of 83%.

Example 5

Under nitrogen protection, [(η ³ -C ₃ H ₅ )PdCl] ₂ (2.1 mg, 0.006 mmol, 2 mol%) and sodium hydride (60% inoil, 12 mg, 0.30 mmol, 1.0 equiv) were suspended in dioxane Ring (1.5 mL), stirred at 25°C for 5 minutes, added a solution of compound 1a (0.3 mmol) in dioxane (0.5 mL), then reacted at 30°C for 2 hours, added saturated aqueous ammonium chloride to stop the reaction, and washed with acetic acid Ethyl ester was extracted, the extracts were combined, dried over sodium sulfate, evaporated to dryness by rotary evaporation, and purified by column chromatography to obtain product 3a with a yield of 65%.

Example 6

Under nitrogen protection, Pd(dppp)Cl ₂ (18 mg, 0.03 mmol, 10 mol%) and sodium hydride (60% in oil, 24 mg, 0.6 mmol, 2 equiv) were suspended in DMA (1.5 mL), stirred at 25°C Add compound 1a (0.3mmol) in DMA (0.5 mL) for 5 minutes, then react at 25°C for 2 hours, add saturated aqueous ammonium chloride solution to stop the reaction, extract with ethyl acetate, combine the extracts, and dry over sodium sulfate , evaporated to dryness by rotary evaporation, and purified by column chromatography to obtain product 3a with a yield of 63%.

Example 7

Under nitrogen protection, Pd(C ₆ H ₅ CN) ₂ Cl ₂ (11.4 mg, 0.03 mmol, 10 mol%) and sodium hydride (60% inoil, 24 mg, 0.6 mmol, 2 equiv) were suspended in DMA (1.5 mL) , stirred at 25°C for 5 minutes, added a solution of compound 1a (0.3 mmol) in DMA (0.5 mL), then reacted at 25°C for 2 hours, added saturated aqueous ammonium chloride solution to stop the reaction, extracted with ethyl acetate, and combined the extracts, Dry over sodium sulfate, evaporate to dryness by rotary evaporation, and purify by column chromatography to obtain product 3a with a yield of 77%.

Example 8

Under nitrogen protection, Pd(OH) ₂ (4.2 mg, 0.03 mmol, 10 mol%) and sodium hydride (60% in oil, 24 mg, 0.6 mmol, 2 equiv) were suspended in DMA (1.5 mL), stirred at 25°C for 5 minutes , add a solution of compound 1a (0.3mmol) in DMA (0.5 mL), then react at 25°C for 2 hours, add saturated aqueous ammonium chloride solution to stop the reaction, extract with ethyl acetate, combine the extracts, dry with sodium sulfate, spin Evaporated to dryness and purified by column chromatography, the product 3a was obtained with a yield of 69%.

Example 9

Under nitrogen protection, palladium chloride (5.3 mg, 0.03 mmol, 10 mol%) and sodium hydride (60% in oil, 24 mg, 0.6 mmol, 2 equiv) were suspended in DMA (1.5 mL), stirred at 25°C for 5 minutes, Add a solution of compound 1b (0.3 mmol) in DMA (0.5 mL), react at 25°C for 2 hours, add saturated aqueous ammonium chloride solution to stop the reaction, extract with ethyl acetate, combine the extracts, dry over sodium sulfate, and rotary evaporate Evaporated to dryness and purified by column chromatography, the product 3b was obtained with a yield of 98%. ¹ H NMR(400 MHz, CDCl ₃ ): δ 7.69 (d, J = 7.6 Hz, 1H), 7.59-7.40 (m, 6H), 7.38-7.29(m, 2H), 3.74 (dd, J = 8.0, 4.3 Hz, 1H), 3.56 (dd, J = 16.9, 3.9 Hz, 1H), 3.37 (s, 3H), 3.13 (dd, J = 16.8, 8.1 Hz, 1H). ¹³ C NMR (151 MHz, CDCl ₃ ): δ202.19, 169.67, 154.41, 143.94, 135.80, 135.10, 129.94, 128.24, 127.95,127.61, 126.46, 124.42, 51.10, 37.92, 61.80. +.

Example 10

Under nitrogen protection, palladium chloride (5.3 mg, 0.03 mmol, 10 mol%) and sodium hydride (60% in oil, 24 mg, 0.6 mmol, 2 equiv) were suspended in DMA (1.5 mL), stirred at 25°C for 5 minutes, Add a solution of compound 1c (0.3 mmol) in DMA (0.5 mL), then react at 25°C for 2 hours, add saturated aqueous ammonium chloride solution to stop the reaction, extract with ethyl acetate, combine the extracts, dry over sodium sulfate, and rotary evaporate Evaporated to dryness and purified by column chromatography, the product 3c was obtained with a yield of 98%. The mixture of enol and keto form, enol/keto = 84/16. ¹ H NMR (400 MHz, CDCl ₃ ): δ7.81 (d, J = 7.6 Hz, 1H, enol), 7.72 (d, J = 7.6 Hz , 1H, keto), 7.63-7.46 (m,2H, enol and keto), 7.44-7.33 (m, 1H, enol and keto), 4.11-3.92 (m, 1H,keto), 3.77-3.68 (m, 1H , keto), 3.58 (s, 2H, enol), 3.12 (dd, J = 17.4, 7.7Hz, 1H, keto), 2.49 (s, 3H, keto), 2.17 (s, 3H, ^enol ). (151 MHz, CDCl ₃ ): δ 201.52 (keto), 199.85 (keto), 191.56, 177.60, 154.24 (keto), 147.63, 138.31, 135.52 (keto), 135.14 (keto), 132.88, 127.76 (keto), 127.76 (keto), ,126.73 (keto), 125.85, 124.61 (keto), 123.28, 110.56, 62.07 (keto), 30.38,29.82 (keto), 28.00 (keto), 21.18. LR-MS (ESI): m/z 175.1 [M+ H]+.

Example 11

Under nitrogen protection, palladium chloride (5.3 mg, 0.03 mmol, 10 mol%) and sodium hydride (60% in oil, 24 mg, 0.6 mmol, 2 equiv) were suspended in DMA (1.5 mL), stirred at 25°C for 5 minutes, Add a solution of compound 1d (0.3 mmol) in DMA (0.5 mL), react at 25°C for 2 hours, add saturated aqueous ammonium chloride to stop the reaction, extract with ethyl acetate, combine the extracts, dry over sodium sulfate, and rotary evaporate Evaporated to dryness and purified by column chromatography, the product 3d was obtained with a yield of 99%. The mixture of enol and keto form, enol/keto = 87/13. ¹ H NMR (400 MHz, CDCl ₃ ): δ15.08 (br, 1H, enol), 8.14 (d, J = 7.6 Hz, 2H, keto) , 8.00-7.92 (m, 2H, enol), 7.89 (d, J = 7.6 Hz, 1H, enol), 7.73 (d, J = 7.6 Hz, 1H, keto), 7.62-7.48 (m, 5H, enol and keto), 7.44 (t, J = 7.2 Hz, 1H, enol), 7.40-7.35 (m,1H, keto), 4.87 (dd, J = 7.4, 2.6 Hz, 1H, keto), 3.94 (s, 2H, enol), 3.90-3.75 (m, 1H, keto), 3.34 (dd, J = 17.1, 7.7 Hz, 1H, keto). ¹³ C NMR (151 MHz,CDCl ₃ ): δ 200.12 (keto), 195.95, 194.40 (keto), 170.91, 154.47 (keto), 148.70, 145.81 (keto), 138.03, 136.43 (keto), 135.41 (keto), 134.94 (keto), 133.68 (keto), 133.47, 131.40, 129.98. 127.83 (keto), 127.59,126.65 (keto), 125.73, 124.77(keto), 123.57, 109.58, 56.69 (keto), 32.37,30.20 (keto). LR-MS (ESI): m/z 237.0 [M+H ]+.

Claims (10)

1. The method for preparing 1,3-dicarbonyl compounds based on the metal hydride/palladium compound system comprises the following steps, under nitrogen protection, the palladium compound and the metal hydride are suspended in a solvent, and then an electron-deficient alkene compound is added, at 0 ℃～100℃ for 0.3～10 hours to get 1,3-dicarbonyl compound. 2. method according to claim 1, is characterized in that, described metal hydride comprises sodium hydride, lithium hydride, potassium hydride, calcium hydride; Described palladium compound comprises palladium chloride, palladium acetate, Pd ₂ (dba) _3. Pd(TFA) ₂ , [(η ³ -C ₃ H ₅ )PdCl] ₂ , Pd(dppp)Cl ₂ , Pd(C ₆ H ₅ CN) ₂ Cl ₂ , Pd(OH) ₂ . 3. The method according to claim 2, wherein the metal hydride is sodium hydride or lithium hydride; the palladium compound is palladium chloride or palladium acetate. 4. The method according to claim 3, characterized in that, the metal hydride is sodium hydride; the palladium compound is palladium chloride. 5. The method according to claim 1, wherein the chemical structural formula of the electron-deficient alkene compound is as follows: R is selected from aryl, alkyl, alkoxy, amine. 6. The method according to claim 1, characterized in that, the molar ratio of the palladium compound, the metal hydride, and the electron-deficient alkene compound is (0.01˜1):(1˜5):1. 7. The method according to claim 6, characterized in that the molar ratio of the palladium compound, the metal hydride, and the electron-deficient alkene compound is (0.05˜0.15):(1˜3):1. 8. The method according to claim 1, characterized in that, after the reaction is finished, add saturated ammonium chloride aqueous solution to stop the reaction, then extract, evaporate to dryness, and purify by column chromatography to obtain the product 1,3-dicarbonyl compound. 9. The method according to claim 1, wherein the solvent is DMA, DMF, THF, DME or dioxane. 10. The method according to claim 1, characterized in that, the temperature of the reaction is 25-60°C; the time of the reaction is 0.3-2 hours.