A method for synthesizing 5-phenyl-5-aroyl-1,3-dioxane compounds

Abstract

The application discloses a chemical synthesis method of 5-phenyl-5-aroyl-1,3-dioxane compound. The method is one-pot reaction of alkyne compound and paraformaldehyde under catalysis of boron trifluoride ether, to generate 5-phenyl-5-aroyl-1,3-dioxane compound. The method has the advantages of mild reaction condition, simple operation, easy-to-obtain raw material, excellent compatibility of substrate functional groups, high reaction yield, low reaction cost and the like, and has high application value.

Description

Technical Field

[0001] This invention relates to a method for synthesizing 5-phenyl-5-aramido-1,3-dioxane compounds. Specifically, it relates to a one-pot reaction of an alkyne compound and paraformaldehyde under the catalysis of boron trifluoride diethyl ether, achieving high yield and high selectivity for the synthesis of 5-phenyl-5-aramido-1,3-dioxane compounds, belonging to the field of organic intermediate synthesis technology. Background Technology

[0002] Compounds containing 1,3-dioxane play an important role in chemical intermediates, fuel additives, and organic synthesis. There are two main traditional methods for synthesizing 1,3-dioxane-based organic compounds. One method uses 1,3-diol and formaldehyde as raw materials, undergoing a condensation reaction under acid catalysis; however, this method is costly. The other method uses olefins and formaldehyde as raw materials, undergoing a condensation reaction under sulfuric acid catalysis; this method is highly polluting, causes severe equipment corrosion, and has a limited range of raw material options.

[0003] Chinese patent CN 103420973 B (2012) discloses a method for synthesizing 1,3-dioxane-based organic compounds. This method uses industrial formaldehyde and a butene-containing four-carbon hydrocarbon as raw materials. Under the action of a solid acidic resin catalyst, the reaction proceeds through a two-stage fixed-bed reactor combined with extraction and distillation, ultimately yielding 1,3-dioxane-based organic compounds through the condensation reaction of formaldehyde and butene. Because this method requires a fixed-bed reactor and solid acidic resin, and involves high reaction temperatures, pressures, and long reaction times, it places very high demands on equipment. Therefore, there is a need to find a low-cost, mild-condition, highly efficient, and easily mass-producible green synthesis method to obtain 1,3-dioxane-based organic compounds. Summary of the Invention

[0004] In view of the deficiencies in the existing methods for synthesizing 1,3-dioxane organic compounds, the present invention aims to provide a method for synthesizing 5-phenyl-5-benzoyl-1,3-dioxane compounds with high reaction yield, low cost, mild conditions, readily available raw materials, and excellent substrate functional group compatibility.

[0005] To achieve the above-mentioned technical objectives, the present invention provides a method for synthesizing 5-phenyl-5-aramid-1,3-dioxane compounds. The method involves reacting an alkyne compound and paraformaldehyde in a one-pot reaction catalyzed by boron trifluoride diethyl ether to generate 5-phenyl-5-aramid-1,3-dioxane compounds.

[0006] The structure of the alkyne compound of formula 1 is as follows:

[0007]

[0008] The 5-phenyl-5-aramid-1,3-dioxane compound has the structure of Formula 2:

[0009]

[0010] in,

[0011] R represents an electron-donating or electron-withdrawing group.

[0012] As a preferred option, R is -H, -OCH3, -CH3, -NO2, -CN, or -COOCH3.

[0013] In the 5-phenyl-5-aramid-1,3-dioxane compound of the present invention, R is introduced by an alkyne compound. Commonly used diphenylalkyne compounds in the prior art are suitable for the synthesis of the 5-phenyl-5-aramid-1,3-dioxane compound of the present invention. R can be an electron-donating group, specifically such as hydrogen, C1-C5 alkyl groups (e.g., methyl, ethyl, butyl, etc.), C1-C5 alkoxy groups (e.g., methoxy, butoxy, etc.), etc. R can also be an electron-withdrawing group, commonly such as nitro, cyano, methyl ester, etc. The position of R on the benzene ring is not limited; it can be ortho, meta, or para, with para being the most preferred.

[0014] As a preferred embodiment, the reaction uses a haloalkane as the reaction medium. While organic solvents such as tetrahydrofuran, ethyl acetate, and acetonitrile can facilitate the reaction, the yield of the target product is not ideal. However, using a haloalkane as the reaction medium significantly improves the yield of the target product, with dichloromethane being the most preferred reaction medium.

[0015] As a preferred embodiment, the molar ratio of the alkyne to paraformaldehyde is 1:1 to 6. The most preferred ratio is 1:4 to 6. With increasing paraformaldehyde dosage, the yield of the target product shows a significant increasing trend, reaching its maximum when the molar ratio is approximately 1:5. Further increasing the paraformaldehyde dosage does not significantly increase the yield of the target product.

[0016] As a preferred embodiment, the molar ratio of the alkyne to boron trifluoride diethyl ether is 1:1 to 2. The most preferred ratio is 1:1.

[0017] As a preferred embodiment, the reaction conditions are: reaction at room temperature for 1–8 hours, with the most preferred being 5–7 hours. As the reaction time increases, the yield of the target product shows a significant increasing trend, reaching its maximum at approximately 6 hours. Further increasing the reaction time does not significantly increase the yield. Therefore, the optimal reaction time is 6 hours.

[0018] This invention uses alkyne compounds as substrates, readily available paraformaldehyde as a carbon source, boron trifluoride diethyl ether as a catalyst, and dichloromethane as a solvent to synthesize 5-phenyl-5-aramid-1,3-dioxane compounds via an alkyne cyclization reaction under stirring at room temperature. The reaction route is as follows:

[0019]

[0020] This invention uses the reaction of diphenylacetylene with paraformaldehyde as an example to specifically illustrate the possible reaction mechanism as follows:

[0021]

[0022] The reaction process is as shown in the above reaction equation. The reaction mainly proceeds through two pathways: In pathway A, in the first step of the reaction, the alkyne is attacked by activated formaldehyde molecules (containing two formaldehyde molecules), yielding a six-membered ring intermediate (A) containing two oxygen atoms. Then, intermediate A undergoes tautomerization and reacts with another formaldehyde molecule to give product 2a. In pathway B, in the first step of the reaction, the alkyne is attacked by activated formaldehyde molecules (containing three formaldehyde molecules), generating an eight-membered ring intermediate (B) containing three oxygen atoms. Then, intermediate B undergoes tautomerization to give product 2a.

[0023] Compared with the prior art, the technical solution of the present invention brings the following beneficial technical effects:

[0024] 1) This invention is the first to use paraformaldehyde as a carbon source to synthesize 5-phenyl-5-aramid-1,3-dioxane compounds with alkynes in the presence of a catalyst, providing a new approach for the synthesis of 5-phenyl-5-aramid-1,3-dioxane compounds.

[0025] 2) The raw materials used in this invention, such as paraformaldehyde and alkynes, are abundant and readily available, and have low cost;

[0026] 3) This invention does not use transition metal catalysts, resulting in high reaction selectivity and high yield.

[0027] 4) The reaction conditions of this invention are mild, do not require anhydrous oxygen treatment, can be carried out at room temperature, are simple to operate, and are conducive to large-scale production. Attached Figure Description

[0028] Figure 1 It is 5-phenyl-5-benzoyl-1,3-dioxane 1 H NMR;

[0029] Figure 2 It is 5-phenyl-5-benzoyl-1,3-dioxane 13C NMR;

[0030] Figure 3 It is 5-phenyl-5-toluamide-1,3-dioxane 1 H NMR;

[0031] Figure 4 It is 5-phenyl-5-toluamide-1,3-dioxane 13 C NMR. Detailed Implementation

[0032] The following specific embodiments are intended to further illustrate the content of the present invention, rather than to limit the scope of protection of the claims of the present invention.

[0033] This invention uses the reaction of diphenylacetylene with paraformaldehyde as an example for specific illustration, and uses the screened optimal reaction conditions as the standard reaction conditions. The specific reaction formula is as follows:

[0034]

[0035] The specific operating steps are as follows: In a 25 mL three-necked round-bottom flask, add diphenylacetylene (0.5 mmol), paraformaldehyde (2.5 mmol), boron trifluoride ether solution (0.5 mmol), and dichloromethane (10 mL) in sequence. Stir the mixture at room temperature for 6 h. After the reaction is complete, add ice water to quench the reaction. Then add 20 mL of dichloromethane to the above reaction solution. Separate the mixture using a separatory funnel. Remove the solvent from the obtained organic layer under reduced pressure. Separate the product by silica gel column chromatography to obtain the yield.

[0036] The following control experimental groups 1-21 are compared and explained using standard reaction conditions as a reference:

[0037]

[0038]

[0039] The table above shows experimental groups 1-7, which investigated the effects of different solvents on the cyclization reaction of diphenylacetylene with paraformaldehyde. The experiments demonstrated that 1,2-dichloromethane, dichloromethane, trichloromethane, carbon tetrachloride, tetrahydrofuran, ethyl acetate, and acetonitrile can all be used for the reaction. However, the choice of solvent significantly affects the yield of the target product. Halogenated hydrocarbons showed better results than common organic solvents such as acetonitrile, tetrahydrofuran, and ethyl acetate, with dichloromethane being the optimal solvent among the halogenated hydrocarbons. Therefore, it can be concluded that dichloromethane is the best solvent for this reaction.

[0040] The effects of Lewis acid catalysts on the cyclization reaction of diphenylacetylene and paraformaldehyde were investigated in experimental groups 1, 8-11 in the table above. The experiments showed that anhydrous aluminum trichloride, anhydrous ferric chloride, trifluoromethanesulfonic acid, trifluoroacetic acid, and boron trifluoride ether could all be used for the reaction. However, the choice of catalyst had a significant impact on the yield of the target product. The effect of boron trifluoride ether was better than that of trifluoromethanesulfonic acid, trifluoroacetic acid, anhydrous aluminum trichloride, and anhydrous ferric chloride in that order. The optimal catalyst was boron trifluoride ether, which could increase the yield of the target product to over 91%.

[0041] The experimental groups 1 and 12-16 in the table above investigated the effect of the amount of paraformaldehyde used on the cyclization reaction between diphenylacetylene and paraformaldehyde. The experiments showed that using 5.0 equivalents of paraformaldehyde is the optimal choice for this reaction, which can increase the yield of the target product to over 91%. If the amount of paraformaldehyde is too low, the ideal yield cannot be achieved, and if the amount of paraformaldehyde is too high, the increase in the yield of the target product is not significant.

[0042] The table above shows that experimental groups 1 and 17-20 investigated the effect of reaction time on the cyclization reaction between diphenylacetylene and paraformaldehyde. When the reaction time was less than 6 hours, the product yield decreased significantly. When the reaction time exceeded 6 hours, the product yield did not increase significantly. The experiment shows that 6 hours is the optimal reaction time for this reaction.

[0043] In the table above, experimental group 21 investigated the effect of the amount of boron trifluoride diethyl ether solution on the cyclization reaction of diphenylacetylene and paraformaldehyde. Increasing the amount of boron trifluoride diethyl ether solution did not significantly improve the product yield. The experiment showed that 1.0 equivalent of boron trifluoride diethyl ether solution is the optimal catalyst amount for this reaction.

[0044] Examples 1-5

[0045] Examples 1-5 below all follow the reaction equations below, mainly to investigate the yield of different substrates under optimal conditions:

[0046]

[0047] The specific operating steps are as follows: In a 25 mL three-necked round-bottom flask, add alkyne (0.5 mmol), paraformaldehyde (2.5 mmol), boron trifluoride ether solution (0.5 mmol), and dichloromethane (10 mL) in sequence. Stir the mixture at room temperature for 6 h. After the reaction is complete, add ice water to quench the reaction. Then add 20 mL of dichloromethane to the above reaction solution. Separate the mixture using a separatory funnel. Remove the solvent from the obtained organic layer under reduced pressure. Separate the product by silica gel column chromatography to obtain the yield.

[0048] Example 1

[0049] Yield 91%, phenyl(5-phenyl-1,3-dioxan-5-yl)methanone

[0050]

[0051] 1 H NMR (400MHz, CDCl3) δ7.45–7.38(m,6H),7.30–7.26(m,4H),4.96(d,J=5.9Hz ,1H),4.85(d,J=6.0Hz,1H),4.70(d,J=11.5Hz,2H),4.21(d,J=11.6Hz,2H).

[0052] 13 C NMR (101MHz, CDCl3) δ200.71,137.36,136.82,131.97,129.48,128.73,128.30,128.11,126.59,94.08,77.33,77.22,77.02,76.70,72.89,53.88.

[0053] Example 2

[0054] Yield 82%, (5-phenyl-1,3-dioxan-5-yl)(p-tolyl)methanone

[0055]

[0056] 1 H NMR (400MHz, CDCl3) δ7.41–7.19(m,7H),7.06(d,J=8.0Hz,2H),4.92(d,J=5.9Hz,1H) ,4.85(d,J=5.9Hz,1H),4.65(d,J=11.5Hz,2H),4.24(d,J=11.5Hz,2H),2.30(s,3H).

[0057] 13 C NMR (101MHz, CDCl3) δ200.01,142.84,137.92,133.85,130.21,129.42,129.11,129.00,12 8.92,128.73,128.28,127.98,126.70,126.39,94.06,77.42,77.11,76.79,73.05,53.75.

[0058] Example 3

[0059] Yield 78%, (5-(4-nitrophenyl)-1,3-dioxan-5-yl)(phenyl)methanone

[0060]

[0061] 1 H NMR (400MHz, CDCl3) δ8.35–8.23(m,2H),7.83–7.68(m,2H),7.52–7.39(m,3H) ,7.38–7.27(m,2H),5.00(d,J=6.0Hz,1H),4.84(d,J=6.0Hz,1H),4.46(s,4H).

[0062] 13 C NMR (101MHz, CDCl3) δ198.88,147.34,146.27,135.41,132.98,128.93,128.65,128.44,124.39,94.05,72.81,53.70.

[0063] Example 4

[0064] Yield 36%, 4-(5-benzoyl-1,3-dioxan-5-yl)benzonitrile

[0065]

[0066] 1 H NMR (400MHz, CDCl3) δ7.77–7.68(m,2H),7.70–7.61(m,2H),7.52–7.38(m,3H),7.30( t,J=7.8Hz,2H),4.97(d,J=6.0Hz,1H),4.84(d,J=6.0Hz,1H),4.43(q,J=11.6Hz,4H).

[0067] 13 C NMR (101MHz, CDCl3) δ199.06,144.11,135.56,133.01,132.87,128.88,128.61,128.17,118.33,111.91,94.03,72.74,53.70.

[0068] Example 5

[0069] Yield 60%, methyl 4-(5-benzoyl-1,3-dioxan-5-yl)benzoate

[0070]

[0071] 1 1H NMR (400MHz,CDCl3) δ 8.15–8.03(m,2H), 7.62–7.49(m,2H), 7.42(d,J=7.2Hz,3H), 7.28(dd,J=6.2,5.3Hz,2H), 4.91(s,2H), 4.59(d,J=11.7Hz,2H), 4.32(d,J=11.7Hz,2H), 3.92(s,3H).

[0072] 13 C NMR(101MHz,CDCl3)δ199.81,166.54,143.07,136.16,132.42,130.57,129.79,128.79,128.44,127.02,94.05,72.77,53.90,52.27.

Claims

1. A method for synthesizing a 5-phenyl-5-aramid-1,3-dioxane compound, characterized in that: Alkyne compounds and paraformaldehyde react in a one-pot reaction catalyzed by boron trifluoride diethyl ether to produce 5-phenyl-5-aramid-1,3-dioxane compounds. The structure of the alkyne formula 1 is as follows: The 5-phenyl-5-aramid-1,3-dioxane compound has the structure of Formula 2: Where R is hydrogen.

2. The method for synthesizing a 5-phenyl-5-aramid-1,3-dioxane compound according to claim 1, characterized in that: The reaction uses a haloalkanes as the reaction medium.

3. The method for synthesizing a 5-phenyl-5-aramid-1,3-dioxane compound according to claim 2, characterized in that: The halohydrocarbon is at least one of 1,2-dichloromethane, dichloromethane, trichloromethane, and carbon tetrachloride.

4. The method for synthesizing a 5-phenyl-5-aramid-1,3-dioxane compound according to any one of claims 1 to 3, characterized in that: The molar ratio of the alkyne compound to paraformaldehyde is 1:1 to 6.

5. The method for synthesizing a 5-phenyl-5-aramid-1,3-dioxane compound according to any one of claims 1 to 3, characterized in that: The molar ratio of the alkyne compound to boron trifluoride ether is 1:1 to 2.

6. The method for synthesizing a 5-phenyl-5-aramid-1,3-dioxane compound according to any one of claims 1 to 3, characterized in that: The reaction conditions are: at room temperature, for 1 to 8 hours.

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