Method for thoroughly reducing aromatic oxides

Abstract

The invention discloses a method for thoroughly reducing aromatic oxides by using ammonia borane, and belongs to the technical field of organic chemistry. Ammonia borane 2 is used as a reducing reagent, a reaction is carried out in the presence of trifluoromethanesulfonic acid (HOTf) and an organic solvent 1, 4-dioxane, carboxyl in aromatic carboxylic acid 1 can be reduced to methyl in one step, a methylation product 3 is obtained, and the method can also be used for thorough reduction of esters, aldehydes, ketones, alcohols and ethers. According to the method, the required temperature is low, the used reagents can be commercially obtained, the method has the advantages of simplicity in operation, high yield, wide substrate application range and the like, and the method is suitable for thoroughly reducing a series of aromatic oxides into methyl or methylene products.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemistry and relates to a method for completely reducing aromatic oxygenates, including carboxylic acids, esters, aldehydes, ketones, ethers, alcohols and epoxides, by using ammonia borane. Background Art

[0002] The reduction of carboxylic acids and their derivatives is of vital importance in organic synthesis, and the most common method is to use metal hydride reducing agents, thereby forming the corresponding alcohol. The reduction of carboxylic acids and their derivatives, such as esters, to the methyl group poses a major challenge in organic synthesis, especially for the synthesis or transformation of versatile compounds such as carbohydrates, nucleosides, and other natural products. Reasons for seeking to perform this reaction include the profound impact of the methyl group on biological activity, the ability to exploit the electronic effects of the ester group prior to reduction, or the ability to create deuterium-labeled toluene derivatives.

[0003] The reduction of carboxylic acids and esters to methyl groups generally involves a multistep reaction, with the first step being reduction to the alcohol, followed by a three-step sequence of functional group interconversion to an alkyl halide and further reduction to the methyl product.

[0004]

[0005] In 2020, it was reported that 1,1,3,3-tetramethyldisiloxane and 1,3-biscyclohexylimidazole tetrafluoroborate (ICy·HBF4) reduced unactivated aromatic methyl esters to tolyl derivatives in the presence of Ni(cod)2. However, this method requires liquid silane, metal catalyst, and the reaction needs to be carried out at 110 degrees Celsius.

[0006]

[0007] Ammonia borane is considered a promising hydrogen storage material, and in the past few years, it has also been used as a convenient and relatively inexpensive reducing agent to develop new green synthetic methods with or without metal catalysts. Recently, it has been applied to the reduction of carbonyls, carboxylic acids, esters, amides and other functional groups in the presence of appropriate catalysts or activators (such as TiCl4 or I2). However, carboxylic acids and esters are usually converted into alcohols or ethers under these conditions. In 2022, a method for reducing aromatic esters to methyl groups using NH3BH3 as a reducing agent and Cp2TiCl2 as a catalyst was reported. This method is also applicable to the general reduction system of various oxygen-containing compounds (carboxylic acids, aldehydes, ketones, alcohols, anhydrides, etc.), but metal catalysts and high temperatures are still required.

[0008]

[0009] Therefore, it is very important to develop methods that are in line with the development direction of green chemistry, using commercially available reagents, easy to operate, and mild conditions to completely reduce aromatic oxygenates. Summary of the invention

[0010] The technical problem solved by the present invention is to provide a method for completely reducing aromatic oxygenates, wherein ammonia borane is used as a reducing agent, and after adding HOTf, a tri-coordinated boron cation is generated in situ, and the aromatic oxygenates are completely reduced in one step. The method has the advantages of cheap and readily available raw materials, good functional group tolerance, mild reaction conditions, etc., and avoids the disadvantages of traditional preparation methods such as many reaction steps, harsh reaction conditions, and the need for metal catalysts.

[0011] In order to solve the above technical problems, the present invention adopts the following technical scheme, a method for completely reducing aromatic oxygenates, comprising the following operations: using aromatic compounds 1A-D and ammonia borane 2 as raw materials, reacting in an organic solvent in the presence of an acid to obtain reduction products 3A-D; the reaction equation is expressed as:

[0012]

[0013] Wherein: Ar is substituted phenyl, ferrocenyl, naphthyl, pyrenyl, thienyl, benzothienyl; the substituent of the substituted phenyl is selected from one or more of hydrogen, C1-C4 alkyl, amine, halogen atom, alkoxy, pyridyl, morpholinyl, piperidyl, thienyl, piperazinyl.

[0014] Furthermore, in the above technical solution, the organic solvent is one of dichloromethane, 1,4-dioxane, diethyl ether, 1,2-dichloroethane, ethylene glycol dimethyl ether, cyclohexane or toluene.

[0015] Furthermore, in the above technical solution, the acid is trifluoromethanesulfonic acid (HOTf) or trimethylsilyl trifluorosulfonate (TMSOTf).

[0016] Furthermore, in the above technical solution, the aromatic carboxylic acid compound 1 can be an ester, aldehyde, ketone, alcohol, ether, or epoxide with a similar structure.

[0017] Furthermore, in the above technical solution, the molar ratio of the compound 1, ammonia borane 2 and trifluoromethanesulfonic acid is 1:3.0-5.0:1.5-2.5.

[0018] Furthermore, in the above technical solution, the reaction temperature is 60°C.

[0019] Furthermore, in the above technical solution, the reaction is carried out in an inert gas.

[0020] Advantageous Effects of the Invention

[0021] (1) The present invention is simple to operate and has mild reaction conditions. Compared with the traditional method, no catalyst or additive is used, and no other reagents or complicated reaction processes need to be added during the synthesis process, and the process operation process is simple;

[0022] (2) The raw materials are cheap and readily available, the reaction time is short, the substrate has a wide range of applicability, the functional group tolerance is good, and the atom economy is high. DETAILED DESCRIPTION

[0023] The present invention is further described in detail below in conjunction with a specific implementation case. This implementation case is implemented on the premise of the technical solution of the present invention, and a detailed implementation method and a specific operation process are given, but the protection scope of the present invention is not limited to the following implementation case.

[0024] Example 1

[0025]

[0026] Taking the reduction of 4-phenylbenzoic acid 1a to 4-methylbiphenyl 3a as an example, the reaction conditions were optimized as follows:

[0027]

[0028]

[0029] After screening, the optimal conditions for reducing 4-phenylbenzoic acid were selected as label 8: the molar ratio of reactants to ammonia borane and trifluoromethanesulfonic acid (HOTf) was 1:3.5:1.75, and the reaction was carried out in 1,4-dioxane solvent at 60°C for 24h. 3a, white solid, 1 H NMR (400MHz, CDCl3) δ7.57(d,J=7.8Hz,2H),7.48(d,J=7.9Hz,2H),7.41(t,J=7.5Hz,2H),7.30(t,J=7.3Hz,1H),7.23(d,J=7.8Hz,2H),2.38(s,3H). 13 C NMR (101MHz, CDCl3) δ141.29,138.49,137.14,129.61,128.84,127.13,127.10,21.23.

[0030] Example 2

[0031] Weigh 0.2 mmol of carboxylic acid (aldehyde, ketone, alcohol, ether, oxirane) and 0.7 mmol of NH3BH3, add to a 35 mL dry pressure tube, and connect to the double row tube. Then add 2 mL of dry 1,4-dioxane and 0.35 mmol of HOTf. Under nitrogen flow, quickly seal the pressure tube with a polytetrafluoroethylene cap, and then heat to The reaction was continued for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, and the reaction mixture was extracted with ethyl acetate (3*11 mL), and the organic phase was dried over anhydrous Na2SO4. The solvent was then removed by rotary evaporation, and the crude product was separated by column chromatography to obtain the corresponding target product. The specific results are as follows:

[0032]

[0033]

[0034] [b] GC yield (internal standard is n-dodecane); [c] separation yield.

[0035] Example 3

[0036] The same reaction conditions as in Example 2 were used, and only the reaction substrate 1 was changed to reaction substrate 4 or 5. The specific results were as follows:

[0037]

[0038] [b] GC yield (internal standard is n-dodecane); [c] separation yield.

[0039] Example 4

[0040] According to the method of Example 2, only the reaction substrate 1 was changed to the reaction substrate 6, and the specific reaction conditions were: 6 (0.2 mmol), 2 (1 mmol), HOTf (0.5 mmol), 1,4-dioxane (2 mL), and the reaction was carried out at 60° C. for 24 h under nitrogen protection; the specific results are as follows:

[0041]

[0042] [b] GC yield (internal standard is n-dodecane); [c] separation yield.

[0043] Example 5

[0044] The same reaction conditions as in Example 2 were used, and only the reaction substrate 1 was changed to reaction substrate 7, 8 or 9. The specific results were as follows:

[0045]

[0046] [b] GC yield (internal standard is n-dodecane); [c] separation yield.

[0047] Representative product characterization data are as follows:

[0048]

[0049] 1-methylferrocene 1 H NMR (400MHz, CDCl3) δ4.07-3.89 (m, 9H), 1.91 (s, 3H). 13 CNMR(101MHz,CDCl3)δ84.07,69.25,68.71,67.21,14.96.

[0050]

[0051] 2-(p-tolyl)thiophene 1 H NMR (400MHz, CDCl3) δ7.53 (d, J = 8.2Hz, 2H), 7.31-7.26 (m, 2H), 7.21 (d, J = 7.9Hz, 2H), 7.09 (dd, J = 5.1, 3.6Hz, 1H), 2.39 (s, 3H). 13 C NMR (101MHz, CDCl3) δ144.74,137.47,131.81,129.69,128.05,126.03,124.40,122.72,21.30.

[0052]

[0053] 2-methyl-5-phenylthiophene 1 H NMR (400MHz, CDCl3) δ7.46 (d, J = 7.9 Hz, 2H), 7.26 (t, J = 7.7 Hz, 2H), 7.18-7.11 (m, 1H), 7.02 (d, J = 3.5 Hz, 1H), 6.64 (d, J = 3.5 Hz, 1H), 2.42 (s, 3H). 13 C NMR (101MHz, CDCl3) δ142.11,139.63,134.84,128.93,127.11,126.32,125.62,123.01,15.59.

[0054]

[0055] 2-methyl-1,1'-biphenyl 1H NMR(400MHz,CDCl3)δ7.56-7.07(m,9H),2.27(s,3H). 13 C NMR(101MHz,CDCl3)δ142.12,142.09,135.47,130.44,129.93,129.33,128.20,127.38,126.89,125.89,20.59.

[0056]

[0057] 1-benzyl-2-methylbenzene 1 H NMR(400MHz,CDCl3)δ7.43-6.84(m,9H),3.97(s,2H),2.23(s,3H). 13 C NMR(101MHz,CDCl3)δ140.53,139.05,136.75,130.42,130.09,128.87,128.52,126.58,126.12,126.05,39.59,19.79.

[0058]

[0059] 4-(p-tolyl)morpholine 1 H NMR(400 MHz,CDCl3)δ7.08(d,J=8.5 Hz,2H),6.82(d,J=8.6 Hz,2H),3.99-3.73(m,4H),3.21-2.95(m,4H),2.27(s,3H). 13 C NMR(101 MHz,CDCl3)δ149.33,129.81,129.63,116.14,67.09,50.03,20.52.

[0060]

[0061] 1-methylpyrene 1 H NMR(400 MHz,CDCl3)δ8.37-7.78(m,9H),3.00(s,3H). 13CNMR(101 MHz,CDCl3)δ132.32,131.59,131.12,129.87,129.32,127.95,127.65,127.21,126.53,125.87,125.00,124.97,124.91,124.85,124.78,123.79,19.88.

[0062]

[0063] 1-methyl-4-phenoxybenzene 1 H NMR(400 MHz,CDCl3)δ7.44-6.86(m,9H),2.37(s,3H). 13 C NMR(101 MHz,CDCl3)δ157.95,154.83,133.02,130.37,129.77,122.92,119.26,118.46,20.84.

[0064]

[0065] (2-(p-tolyl)ethene-1,1,2-triyl)tribenzene 1 H NMR(400 MHz,CDCl3)δ7.19-6.96(m,15H),6.92(s,4H),2.26(s,3H). 13 C NMR(101 MHz,CDCl3)δ144.08,144.06,141.04,140.87,140.60,136.18,131.49,131.45,131.35,128.51,127.79,127.73,126.46,126.41,21.32.

[0066]

[0067] 1-(p-tolyl)piperidine 1 H NMR(400 MHz,CDCl3)δ7.09(d,J=8.2 Hz,2H),6.90(d,J=8.5 Hz,2H),3.16-3.08(m,4H),2.30(s,3H),1.74(p,J=5.7 Hz,4H),1.64-1.55(m,2H). 13C NMR(101 MHz,CDCl3)δ150.40,129.63,128.86,117.08,51.44,26.07,24.41,20.54.

[0068]

[0069] 1-methyl-4-(p-tolyl)piperazine 1 H NMR(400 MHz,CDCl3)δ7.08(d,J=8.3 Hz,2H),6.86(d,J=8.6 Hz,2H),3.23-3.10(m,4H),2.64-2.53(m,4H),2.35(s,3H),2.27(s,3H). 13 C NMR(101 MHz,CDCl3)δ149.30,129.75,129.35,116.52,55.30,49.77,46.26,20.54.

[0070]

[0071] 1-(4-ethylphenyl)piperazine 1 H NMR(400MHz,CDCl3)δ7.12(d,J=8.1Hz,2H),6.84(d,J=8.2Hz,2H),3.36(d,J=15.8Hz,8H),2.58(q,J=7.5Hz,2H),1.21(d,J=15.1Hz,3H). 13 C NMR(101MHz,CDCl3)δ148.11,137.85,128.84,117.59,47.44,44.34,28.06,15.76.

[0072]

[0073] 4-methyl-N,N-diphenylaniline 1 H NMR(400MHz,CDCl3)δ7.17-7.10(m,4H),7.04-6.84(m,10H),2.23(s,3H). 13 C NMR(101MHz,CDCl3)δ148.17,145.38,132.87,130.05,129.24,125.08,123.73,122.35,20.97.

[0074]

[0075] 4-fluoro-4'-methyl-1,1'-biphenyl 1 H NMR (400MHz, CDCl3) δ7.44(dd,J=8.6,5.5Hz,2H),7.35(d,J=7.8Hz,2H),7.16(d,J=8.0Hz,2H),7.02(t,J=8.7Hz,2H),2.31(s,3H). 19 F NMR (376MHz, CDCl3) δ-116.28. 13 C NMR (101MHz, CDCl3) δ162.46 (d, J = 246.4Hz), 137.56, 137.45 (d, J = 3.03Hz), 1 37.18,129.68,128.60(d,J=8.08Hz),127.00,115.68(d,J=22.22Hz),21.20.

[0076] The above are only preferred embodiments of the present invention. It should be noted that the above preferred embodiments should not be regarded as limiting the present invention, and the protection scope of the present invention should be based on the scope defined by the claims. For ordinary technicians in this technical field, several improvements and modifications can be made without departing from the spirit and scope of the present invention, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A method for completely reducing aromatic oxygenates using ammonia borane, characterized in that: The method comprises the following steps: using aromatic compounds 1A-D and ammonia borane 2 as raw materials, reacting in an organic solvent in the presence of an acid to obtain reduction products 3A-D; the reaction equation is expressed as: Wherein: Ar is substituted phenyl, ferrocenyl, naphthyl, pyrenyl, thienyl, benzothienyl; the substituent of the substituted phenyl is selected from one or more of hydrogen, C1-C4 alkyl, amine, halogen atom, alkoxy, pyridyl, morpholinyl, piperidyl, thienyl, piperazinyl.

2. The method for completely reducing aromatic oxygenates using ammonia borane according to claim 1, characterized in that: The organic solvent is selected from dichloromethane, 1,4-dioxane, diethyl ether, 1,2-dichloroethane, ethylene glycol dimethyl ether, cyclohexane or toluene.

3. The method for completely reducing aromatic oxygenates using ammonia borane according to claim 1, characterized in that: The acid is trifluoromethanesulfonic acid or trimethylsilyl trifluorosulfonate.

4. The method for completely reducing aromatic oxygenates using ammonia borane according to claim 1, characterized in that: The molar ratio of the compound 1, ammonia borane 2 and trifluoromethanesulfonic acid is 1:3.0-5.0:1.5-2.

5.

5. The method for completely reducing aromatic oxygenates using ammonia borane according to claim 1, characterized in that: The reaction temperature is 40-80°C.

6. The method for completely reducing aromatic oxygenates using ammonia borane according to claim 1, characterized in that: The reaction is carried out in an inert gas.

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