A method for synthesizing organic acetylenic esters

Abstract

The application discloses a method for synthesizing organic acetylide ester through a palladium catalytic reaction and belongs to the field of organic synthesis. The organic acetylide ester is obtained through a cross-coupling reaction in the presence of a palladium catalyst, a phosphine ligand and an alkali, with terminal alkyne and di-tert-butyl dicarbonate as raw materials. The method has the advantages of high reaction yield, wide substrate range, good functional group compatibility, and the advantages of non-toxic and easy-to-obtain carbonyl source, simple operation steps and mild reaction conditions.

Description

Technical Field

[0001] This invention relates to the preparation of compounds, belonging to the field of organic synthesis, and specifically to a method for preparing organic alkyne esters using terminal alkynes and di-tert-butyl dicarbonate as raw materials under palladium catalysis. Background Technology

[0002] Organic alkynyl esters are common precursors for the synthesis of drug molecules, natural products, and bioactive molecules. They possess unique electron-deficient conjugated triple bond structures, allowing for the direct construction of diverse and complex molecular skeletons through simple chemical reactions. Therefore, the synthesis of organic alkynyl esters has long been a focus of chemists. Among these, the synthetic strategy of directly synthesizing organic alkynyl esters from terminal alkynes via alkoxycarbonylation under transition metal catalysis has gained favor in recent years.

[0003] To date, representative synthetic routes include: (1) as described in Formula 1, the synthesis of organic alkynyl esters from a palladium-catalyzed tripoleon reaction with CO and an alkyl alcohol. This route uses toxic CO gas as the carbonyl source and requires the addition of an oxidant to proceed smoothly; (2) as described in Formula 2, the reaction of a terminal alkyne with CO2 and an alkyl halide to generate organic alkynyl esters under the catalysis of transition metal copper or silver. This route uses relatively environmentally friendly CO2 as the carbonyl source, but the tripoleon reaction is more complex, and using a gas as the carbonyl source often requires higher reaction pressures, posing a higher risk.

[0004]

[0005] This invention provides a novel method for directly converting terminal alkynes into organic alkyne esters using di-tert-butyl dicarbonate as the carbonyl source under palladium catalysis. This method offers high reaction yields, a broad substrate range, good functional group compatibility, and advantages such as readily available and non-toxic carbonyl sources, simple operation steps, and mild reaction conditions. Summary of the Invention

[0006] This invention addresses the shortcomings of existing methods for synthesizing organic alkynyl esters, such as the need for toxic gases as carbonyl sources, cumbersome procedures, and the requirement for high-pressure environments. This invention provides a method for synthesizing organic alkynyl esters that is mild, uses readily available raw materials, does not require toxic carbonyl sources, and is simple to operate.

[0007] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0008] A method for synthesizing an organic acetylacetic ester, characterized in that: using terminal alkynes and di-tert-butyl dicarbonate as raw materials, the reaction is carried out in an organic solvent under heating conditions in the presence of a palladium catalyst, a phosphine ligand, and a base, according to the general formula shown in the figure, to obtain the corresponding organic acetylacetic ester compound:

[0009]

[0010] R is an aryl, heterocyclic, or alkyl substituent.

[0011] Furthermore, in the above technical solution, the palladium catalyst is selected from one of Pd(OAc)2, Pd(TFA)2, Pd2(dba)3, PdCl2, and Pd(PPh3)4. The preferred catalyst is Pd(OAc)2.

[0012] Furthermore, in the above technical solution, the phosphine ligand is selected from one of XPhos (L1), RuPhos (L2), BrettPhos (L3), XantPhos (L4), and PPh3 (L5). XPhos (L1) is the preferred ligand. The ligand structure is shown in the figure below:

[0013]

[0014] Furthermore, in the above technical solution, the alkali is selected from one of sodium carbonate, potassium carbonate, cesium fluoride, triethylamine, diisopropylethylamine, and pyridine. Pyridine is preferred as the alkali.

[0015] Furthermore, in the above technical solution, the organic solvent is selected from one of 1,4-dioxane, acetonitrile, tetrahydrofuran, toluene, dimethyl sulfoxide, and N,N-dimethylformamide. The preferred solvent is 1,4-dioxane.

[0016] Furthermore, in the above technical solution, the preferred molar amount of palladium catalyst is 5% of the molar amount of terminal alkyne.

[0017] Furthermore, in the above technical solution, the preferred molar amount of phosphine ligand is 20% of the molar amount of terminal alkyne.

[0018] Furthermore, in the above technical solution, the preferred molar amount of alkali is twice the molar amount of terminal alkyne.

[0019] Furthermore, in the above technical solution, the preferred molar amount of di-tert-butyl dicarbonate is twice the molar amount of the terminal alkyne.

[0020] Furthermore, in the above technical solution, the preferred reaction temperature is 80°C, the preferred reaction atmosphere is argon protection, and the preferred reaction time is 24 hours.

[0021] The method provided by this invention uses terminal alkynes and di-tert-butyl dicarbonate as raw materials, and reacts them in an organic solvent under heating in the presence of a palladium catalyst, a phosphine ligand, and a base to obtain the corresponding organic alkyne esters. This method eliminates the need for toxic carbonyl sources, does not require high-pressure reactions, is simple to operate, uses readily available raw materials, operates under mild conditions, and exhibits a broad substrate range and good functional group compatibility. Detailed Implementation

[0022] To further illustrate the present invention, preferred embodiments are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, and not for limiting the scope of the claims of the present invention. All other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0024] General Procedure A:

[0025] Terminal alkynes (1.0 equivalent, 0.3 mmol), di-tert-butyl dicarbonate (2 equivalent, 0.6 mmol), Pd(OAc)₂ (5 mol%), and XPhos (20 mol%) were placed in a transparent Schlenk tube equipped with a magnetic stir bar. The tube was evacuated and purged with argon (three times). Under argon atmosphere, pyridine (2 equivalent, 0.6 mmol) and anhydrous 1,4-dioxane (1 mL) were added to the solids via a gas-tight syringe. The reaction mixture was stirred at 80 °C for 24 hours. The reaction mixture was then thoroughly mixed with ethyl acetate, concentrated under vacuum, and separated by silica gel rapid column chromatography to obtain the product (petroleum ether / ethyl acetate = 100:1 to 5:1).

[0026] Example 1: Preparation of tert-butyl 3-phenylpropionate

[0027] Reaction formula:

[0028]

[0029] Using standard procedure A, a yellow oily liquid was obtained in 85% yield. NMR results: 1 H NMR (400MHz, CDCl3) δ7.59–7.53(m,2H),7.45–7.39(m,1H),7.39–7.33(m,2H),1.55(s,9H). 13C NMR (101MHz, CDCl3) δ153.15,132.86,130.31,128.49,119.99,83.79,83.51,82.04,28.07.

[0030] Example 2: Preparation of tert-butyl 3-(2-methylphenyl)propionate

[0031] Reaction formula:

[0032]

[0033] Using standard procedure A, a yellow oily liquid was obtained with a yield of 84%. NMR results: 1 H NMR (400MHz, CDCl3) δ7.55(dd,J=1.1,7.7Hz,1H),7.33(td,J=1.1,7.4Hz,1H),7.27–7.16(m,2H),2.51(s,3H),1.57(s,9H). 13 C NMR (101MHz, CDCl3) δ153.31,142.08,133.23,130.27,129.67,125.69,119.81,85.77,83.33,82.86,28.09,20.55.

[0034] Example 3: Preparation of tert-butyl 3-(3-methoxyphenyl)propionate

[0035] Reaction formula:

[0036]

[0037] Using standard procedure A, a yellow oily liquid was obtained with a yield of 78%. NMR results: 1 H NMR (600MHz, CDCl3) δ7.28–7.25(m,1H),7.16(d,J=7.6Hz,1H),7.09–7.07(m,1H),6.99–6.96(m,1H),3.80(s,3H),1.55(s,9H). 13 C NMR (151MHz, CDCl3) δ159.33,153.10,129.59,125.39,120.92,117.33,117.21,83.72,83.54,81.74,55.35,28.07.

[0038] Example 4: Preparation of tert-butyl 3-(4-ethoxyphenyl)propionate

[0039] Reaction formula:

[0040]

[0041] Using standard procedure A, a yellow oily liquid was obtained with a yield of 67%. NMR results: 1 H NMR (600MHz, CDCl3) δ7.51 (d, J = 8.8Hz, 2H), 6.85 (d, J = 8.8Hz, 2H), 4.07–4.02 (m, 2H), 1.54 (s, 9H), 1.42 (t, J = 7.0Hz, 3H). 13 C NMR (151MHz, CDCl3) δ160.68,153.45,134.77,114.66,111.58,84.66,83.15,81.39,63.65,28.10,14.67.

[0042] Example 5: Preparation of tert-butyl 3-(4-(tert-butyl)phenyl)propionate

[0043] Reaction formula:

[0044]

[0045] Using standard procedure A, a yellow oily liquid was obtained in 75% yield. NMR results: 1 H NMR (400MHz, CDCl3) δ7.53 (d, J = 8.6 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 1.57 (s, 9H), 1.33 (s, 9H). 13 C NMR (101MHz, CDCl3) δ153.91,153.33,132.75,125.54,116.88,84.30,83.32,81.66,35.00,31.07,28.09.

[0046] Example 6: Preparation of tert-butyl 3-(4-(trifluoromethyl)phenyl)propionate

[0047] Reaction formula:

[0048]

[0049] Using standard procedure A, a yellow oily liquid was obtained with a yield of 61%. NMR results: 1 H NMR (600MHz, CDCl3) δ7.68 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 1.55 (s, 9H). 13C NMR (151MHz, CDCl3) δ152.62, 133.02, 132.01, 131.80, 125.45 (q, J = 3.7Hz), 123.88, 84.07, 83.66, 81.63, 28.04. 19 F NMR (565MHz, CDCl3) δ -63.15.

[0050] Example 7: Preparation of tert-butyl 3-(2-fluorophenyl)propionate

[0051] Reaction formula:

[0052]

[0053] Using standard procedure A, a yellow oily liquid was obtained with a yield of 77%. NMR results: 1 H NMR (600MHz, CDCl3) δ7.56–7.52(m,1H),7.44–7.39(m,1H),7.16–7.09(m,2H),1.55(s,9H). 13 C NMR (151MHz, CDCl3) δ164.41, 162.72, 152.73, 134.50, 132.22 (d, J = 8.1Hz), 12 4.17(d,J=3.8Hz),115.86,115.73,108.89(d,J=15.3Hz),86.54,83.77,28.04. 19 F NMR (565MHz, CDCl3) δ -107.58.

[0054] Example 8: Preparation of tert-butyl 3-(2-naphthyl)propionate

[0055] Reaction formula:

[0056]

[0057] Using standard procedure A, a white solid was obtained with a yield of 77%. NMR results: 1 H NMR (400MHz, CDCl3) δ8.13(s,1H),7.84–7.78(m,3H),7.58–7.49(m,3H),1.56(s,9H). 13 CNMR(151MHz, CDCl3)δ159.33,153.10,129.59,125.40,120.93,117.33,117.21,83.72,83.53,81.74,55.35,28.07.

[0058] Example 9: Preparation of tert-butyl 3-(4-methoxycarbonylphenyl)propionate

[0059] Reaction formula:

[0060]

[0061] Using standard procedure A, a yellow oily liquid was obtained with a yield of 71%. NMR results: 1 H NMR (600MHz, CDCl3) δ8.03 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 3.93 (s, 3H), 1.55 (s, 9H). 13 C NMR (151MHz, CDCl3) δ166.13,152.72,132.66,131.41,129.55,124.55,84.05,83.93,82.32,52.38,28.04.

[0062] Example 10: Preparation of tert-butyl 3-(4-formylphenyl)propionate

[0063] Reaction formula:

[0064]

[0065] Using standard procedure A, a white solid was obtained with a yield of 51%. NMR results: 1 H NMR (600MHz, CDCl3) δ10.04 (s, 1H), 7.88 (d, J = 8.1Hz, 2H), 7.72 (d, J = 8.1Hz, 2H), 1.56 (s, 9H). 13 C NMR (151MHz, CDCl3) δ191.15,152.60,133.25,132.74,130.12,129.49,84.74,84.14,81.94,28.04.

[0066] Example 11: Preparation of tert-butyl 3-(4-((tert-butoxycarbonyl)oxy)phenyl)propionate

[0067] Reaction formula:

[0068]

[0069] Using standard procedure A, a yellow solid was obtained with a yield of 52%. NMR results: 1H NMR (600MHz, CDCl3) δ7.44–7.39(m,2H),7.36(t,J=7.9Hz,1H),7.25–7.22(m,1H),1.56(s,9H),1.54(s,9H). 13 C NMR (151MHz, CDCl3) δ152.88,151.39,150.90,130.14,129.55,125.61,123.55,121.26,84.05,83.68,82.47,82.45,28.05,27.67.

[0070] Example 12: Preparation of tert-butyl 3-(3-thienyl)propionate

[0071] Reaction formula:

[0072]

[0073] Using standard procedure A, a yellow oily liquid was obtained in 80% yield. NMR results: 1 H NMR (600MHz, CDCl3) δ7.73–7.70(m,1H),7.31–7.29(m,1H),7.23–7.20(m,1H),1.54(s,9H). 13 C NMR (151MHz, CDCl3) δ153.17,133.20,130.20,125.89,119.22,83.50,82.02,79.26,28.08.

[0074] Example 13: Preparation of tert-butyl 3-(3-pyridyl)propionate

[0075] Reaction formula:

[0076]

[0077] Using standard procedure A, a yellow oily liquid was obtained with a yield of 68%. NMR results: 1 H NMR (600MHz, CDCl3) δ8.79 (s, 1H), 8.64 (d, J = 4.0Hz, 1H), 7.88–7.84 (m, 1H), 7.34–7.30 (m, 1H), 1.55 (s, 9H). 13 C NMR (151MHz, CDCl3) δ153.20,152.54,150.37,139.70,123.12,117.42,84.87,84.06,80.06,28.03.

[0078] Example 14: Preparation of tert-butyl 6-chloro-2-hexyneic acid

[0079] Reaction formula:

[0080]

[0081] Using standard procedure A, a yellow oily liquid was obtained in 53% yield. NMR results: 1 H NMR (600MHz, CDCl3) δ3.65(t,J=6.3Hz,2H),2.52(t,J=6.9Hz,2H),2.06–2.00(m,2H),1.49(s,9H). 13 CNMR (151MHz, CDCl3) δ152.66,84.61,83.23,75.21,43.31,30.37,28.00,16.09.

[0082] Example 15. Preparation of tert-butyl 4-(3-(tert-butoxy)-3-oxopropyl-1-yn-1-yl)piperidine-1-carboxylic acid: Reaction formula:

[0083]

[0084] Using standard procedure A, a white solid was obtained with a yield of 72%. NMR results: 1 H NMR (600MHz, CDCl3) δ3.64(s,2H),3.10(t,J=11.1Hz,2H),2.64–2.58(m,1H),1.73(s,2H),1.61–1.51(m,2H),1.42(s,9H),1.38(s,9H). 13 C NMR (151MHz, CDCl3)δ

[0085] 154.65,152.79,87.64,83.15,79.64,75.54,30.36,28.40,27.98,26.93.

[0086] The foregoing provides a detailed description of a palladium-catalyzed method for synthesizing organic acetylacetic esters. Specific examples have been used to illustrate the principles and implementation methods of the invention. These examples are merely illustrative and are intended to aid in understanding the method and its core concepts. It should be noted that those skilled in the art can make various improvements and modifications to the invention without departing from its principles, and these improvements and modifications also fall within the scope of protection of the claims.

Claims

1. A method for synthesizing an organic acetylacetic ester, characterized in that: Using terminal alkynes and di-tert-butyl dicarbonate as raw materials, the reaction proceeds under heating conditions in an organic solvent in the presence of a palladium catalyst, a phosphine ligand, and a base, according to the following reaction formula, to obtain the corresponding organic alkyne ester compounds: Wherein R is phenyl, 2-methylphenyl, 3-methoxyphenyl, 4-ethoxyphenyl, 4-tert-butylphenyl, 4-trifluoromethylphenyl, 2-fluorophenyl, 4-methoxycarbonylphenyl, 4-formylphenyl, 4-((tert-butoxycarbonyl)oxy)phenyl or 3-chloropropyl.

2. The method according to claim 1, characterized in that: The molar amount of the palladium catalyst is 5% of the molar amount of the terminal alkyne.

3. The method according to claim 1, characterized in that: The molar amount of the phosphine ligand is 20% of the molar amount of the terminal alkyne.

4. The method according to claim 1, characterized in that: The molar amount of the alkali is twice the molar amount of the terminal alkyne.

5. The method according to claim 1, characterized in that: The molar amount of di-tert-butyl dicarbonate is twice the molar amount of the terminal alkyne.

6. The method according to claim 1, characterized in that: The reaction was carried out at 80°C under an argon atmosphere for 24 hours.

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