A photochemical synthesis method of formanilide compounds

Abstract

The application discloses a photochemical synthesis method of formanilide compounds. The method uses aryl halide compounds as raw materials, and performs selective C-X bond formamidation on the aryl halide compounds in the presence of formamide, a catalyst and an alkali, so that formanilide compounds are obtained with high selectivity. The method has the advantages of high efficiency, mild reaction condition, convenient operation, relatively short reaction time, less by-products and the like.

Description

Technical Field

[0001] This invention relates to a photochemical synthesis method for formamide compounds, which synthesizes formamide compounds by selectively formamidifying the CX bond of aryl halogen compounds, and belongs to the field of organic synthesis. Background Technology

[0002] Primary and heteroaromatic formamides are important compounds in organic and biochemistry due to their wide applications in organic synthesis, detergents, lubricants, pharmaceuticals, and pesticides. In medicinal chemistry, amide groups are common in drug compounds and have a crucial influence on the regulation of biological activity and pharmacokinetic properties. In particular, unprotected formamide fragments serve as multifunctional intermediates in synthetic chemistry and are widely found in pharmaceuticals and other functional materials.

[0003] Traditional methods for synthesizing formamide anilines typically involve reacting aniline with a formylation reagent (such as formic acid, formic anhydride, or formyl chloride). However, these methods have several drawbacks: some require low temperatures (usually below 0°C) and anhydrous conditions, increasing operational complexity; reagents such as phosphorus oxychloride are prone to decomposition and explosion upon contact with water, and are highly toxic, posing health risks to operators; some formylation reagents (such as N-(diethylcarbamoyl)-N-methoxyformamide) are expensive, leading to increased production costs; and traditional methods may generate numerous byproducts, reducing atom utilization and contradicting green chemistry principles. Other methods for synthesizing formamide compounds include transition metal-catalyzed reactions using formamide as a substrate, but these methods still have limitations, including the use of precious metals, the need for high-temperature, high-pressure, and strongly acidic / alkaline environments.

[0004] In recent years, the combination of transition metal catalysis and photoelectrocatalysis in organic synthesis has attracted widespread attention. The cross-coupling conditions of this dual-catalytic system are typically very mild, and bond formation exhibits high chemoselectivity and significant functional group tolerance. Xue and colleagues reported the photoinduced nickel-catalyzed CN-coupling of aryl chlorides, which successfully constructed diverse primary and secondary amides, but the reaction still required high temperatures, increasing energy consumption. Therefore, it is necessary to develop a method for the high-yield preparation of formaniline compounds using inexpensive raw materials, with high atom economy, and under mild conditions. Summary of the Invention

[0005] This invention addresses the shortcomings of existing synthetic routes by providing a photochemical synthesis method for formamide compounds. It utilizes nickel and thioxanthone to synergistically catalyze the formamidation reaction of aryl halides, offering advantages such as readily available raw materials, simple process, mild conditions, high yield, broad substrate range, and fewer byproducts.

[0006] The present invention discloses a photochemical synthesis method for formamide compounds, which uses aryl halides as raw materials and carries out a photocatalytic reaction in the presence of a nickel catalyst, a photocatalyst, a base, and formamide. After separation and purification, formamide compounds are obtained.

[0007] The structural formula of the aryl halide is:

[0008] ;

[0009] Wherein: R is selected from H, halogen, alkyl, alkoxy, aryl, sulfonamide, acyl, ester, aldehyde, trimethylsilyl, cyano, or substituents of the above groups; X is Cl, Br, or I. The substituents include conventional substitution methods such as heteroatom substitution and halogen substitution.

[0010] For example, R can be a group such as H, chlorine, methyl, trifluoromethoxy, phenyl, acetyl, ester, aldehyde, trimethylsilyl, tert-butyl, or cyano.

[0011] Specifically, aryl halide 1a is dissolved in a solvent under a nitrogen atmosphere and reacted in a photoreactor in the presence of a nickel catalyst, a photocatalyst, a base, and formamide 2a. After the reaction is completed, the product is separated and purified to obtain the target product 3a.

[0012] The reaction route is shown below:

[0013]

[0014] The reaction wavelength of the synthesis method of the present invention is 365-425 nm, preferably 395 nm, and the reaction time is 12-24 h.

[0015] The nickel catalyst is selected from nickel dichloride, nickel dibromide, nickel acetate tetrahydrate, 1,3-bis(diphenylphosphine) nickel dichloride, or nickel trifluoromethanesulfonate, and the amount of nickel catalyst added is 5 mol%-50 mol% (calculated as aryl halides).

[0016] The photocatalyst is selected from thioxanthone, 4CzIPN, 4DPAIPN, tris(2-phenylpyridine)iridium or Ir[dF(CF3)ppy]2(dtbbpy)PF6, etc., and the amount of the catalyst added is 1 mol%-20 mol% (calculated as aryl halide).

[0017] The alkali is at least one of sodium hydroxide, potassium tert-butoxide, dipotassium hydrogen phosphate, cesium carbonate, potassium acetate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and sodium carbonate, and is added in an amount of 1-3 times the equivalent (calculated as aryl halides).

[0018] The solvent is dimethyl sulfoxide, acetonitrile, ethyl formate, acetone, ethyl acetate, or dibutyl ketone.

[0019] The separation and purification process involves adding water to the reaction solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, removing the solvent by rotary evaporation, and then purifying by column chromatography. The eluent for column chromatography is petroleum ether:ethyl acetate = 5:1 ~ 1:1, v / v, which yields the target product.

[0020] The beneficial effects of this invention are reflected in:

[0021] 1. The synthesis method of the present invention has the characteristics of low raw material cost, low toxicity, and green environmental protection.

[0022] 2. The synthesis method of the present invention has wide substrate applicability, relatively high yield, few by-products, compatibility with multiple functional groups, and is applicable to aryl halides with various substituents. Detailed Implementation

[0023] To further illustrate the features and advantages of the present invention, the technical solution of the present invention is described below with reference to specific embodiments. However, the following embodiments are only for further illustration of the present invention and are not intended to limit the present invention.

[0024] In the synthesis process of this invention, some reaction conditions were optimized and screened as follows:

[0025]

[0026]

[0027] For the above reaction, we used p-4-bromoacetophenone (1a) and formamide (2a) as model substrates, Ni(OAc)₂·4H₂O as a metal catalyst, 4,4'-di-tert-butyl-2,2'-dipyridine as a ligand, sodium bicarbonate as a base, and ethyl acetate as a solvent. Different photocatalysts were screened to synthesize the target compound. Through screening different photocatalysts, benzophenone, 4CzIPN, 4DPAIPN, tris(2-phenylpyridine)iridium, Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆, or thioxanthone all produced the target product, with thioxanthone showing the best reaction performance.

[0028]

[0029]

[0030] After screening different photocatalysts, the metallic nickel catalysts used in the reaction were also screened. According to the experimental results, the target product was generated using catalysts such as nickel dichloride, nickel dibromide, nickel acetate tetrahydrate, 1,3-bis(diphenylphosphine) nickel dichloride, or nickel trifluoromethanesulfonate. Among them, nickel acetate tetrahydrate was the catalyst with the best reaction effect.

[0031]

[0032]

[0033] By screening different solvents, the target product was generated in acetonitrile, acetone, dimethyl sulfoxide, ethyl formate and ethyl acetate, among which ethyl acetate was the solvent with the best reaction effect.

[0034]

[0035]

[0036] After screening different solvents in the reaction system, different types of bases were also screened. Sodium bicarbonate at 2.0 equivalents yielded 80% of the target product. For the reaction system, using organic bases did not significantly improve the reaction efficiency, while using inorganic bases yielded the target product. Using potassium and sodium salts, the reaction yield mostly reached over 60%. In summary, after screening the bases, the weak base sodium bicarbonate was the best choice for the reaction system, achieving an 80% yield.

[0037]

[0038]

[0039] The wavelength of the light source in the reaction conditions was screened, with a wavelength range of 365-425nm. According to the screening results, the reaction efficiency was best when the light source wavelength was 395nm, and the yield of the target product could reach 80%.

[0040] The following specific examples will further illustrate this point.

[0041] Example 1:

[0042]

[0043] To a 25 mL transparent Schlenk tube equipped with a magnetic stir bar, the following were added: 4-bromoacetophenone (1a) (0.2 mmol), formamide (2a) (0.5 mL), sodium bicarbonate (0.4 mmol), nickel catalyst Ni(OAc)₂·4H₂O (0.02 mmol, 10 mol%) and its ligand dtbpy (0.02 mmol, 10 mol%), and thioxanthone photocatalyst (0.02 mmol, 10 mol%). 1.5 mL of ethyl acetate was added under a nitrogen atmosphere. The reaction tube was fixed on a 395 nm wavelength photoreactor, and the reaction was carried out at room temperature for 12 h. The mixture was then extracted with water and ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a white solid (3a) (27 mg, 82%). The NMR data of this compound are as follows: 1 H NMR (600 MHz, DMSO-d6) δ 9.59 (s, 0.71H), 9.52 (d, J = 10.7 Hz,0.26H), 8.04 (d, J = 9.6 Hz, 0.23H), 7.42 (s, 0.67H), 6.98 (t, J = 9.6 Hz,2H), 6.78 (d, J = 8.6 Hz, 1.37H), 6.37 (d, J = 8.4 Hz, 0.47H), 1.58 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 196.90, 196.85, 163.00, 160.57, 143.30, 142.85,132.48, 132.42, 130.42, 129.99, 118.95, 116.71, 26.84, 26.80.

[0044] Example 2:

[0045]

[0046] Bromobenzene (1b) was used instead of 4-bromoacetophenone (1a), otherwise the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a yellow oil (3b) (16 mg, 66%). The NMR data of this compound are as follows: 1HNMR (600 MHz, Chloroform-d) δ 8.74 (s, 0.52H), 8.56 (s, 0.52H), 8.37 (s,0.49H), 7.60 (s, 0.36H), 7.55 (d, J = 7.3 Hz, 1H), 7.39 – 7.29 (m, 2H), 7.19 (t, J = 7.5 Hz, 0.49H), 7.14 (t, J = 7.5 Hz, 0.40H), 7.10 (d, J = 5.7 Hz, 1H). 13 C NMR (151 MHz, Chloroform-d) δ 163.14, 159.68, 137.04, 136.83, 129.73,129.06, 125.26, 124.77, 120.15, 118.77.

[0047] Example 3:

[0048]

[0049] 4-Bromoacetophenone (1a) was replaced with p-chlorobromobenzene (1c), otherwise the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a white solid (3c) (23 mg, 72%). The NMR data of this compound are as follows: 1 H NMR(600 MHz, Chloroform-d) δ 8.66 (d, J = 9.8 Hz, 0.54H), 8.55 (s, 0.46H), 8.36(s, 0.71H), 7.61 (s, 0.62H), 7.49 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 8.7 Hz, 1H). 13 C NMR (151 MHz, Chloroform-d) δ 162.77, 159.33, 135.47, 135.35, 130.71, 129.81, 129.09,121.29, 120.03.

[0050] Example 4:

[0051]

[0052] p-Cyanobromene (1d) was used instead of 4-bromoacetophenone (1a), otherwise the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a yellow solid (3d) (23 mg, 78%). The NMR data of this compound are as follows: 1 HNMR (600 MHz, DMSO-d6) δ 10.63 (s, 0.75H), 10.52 (d, J = 10.4 Hz, 0.24H), 8.98 (d, J = 10.6 Hz, 0.24H), 8.36 (s, 0.75H), 7.77 (q, J = 8.6 Hz, 3.5H),7.37 (d, J = 8.3 Hz, 0.5H). 13 C NMR (151 MHz, DMSO-d6) δ 163.12, 160.86,143.34, 142.74, 134.24, 133.86, 119.74, 119.40, 119.38, 117.50, 105.88,105.66

[0053] Example 5:

[0054]

[0055] 4-(trifluoromethoxy)bromobenzene (1e) was used instead of 4-bromoacetophenone (1a), otherwise the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a yellow oil (3e) (30 mg, 73%). The NMR data of this compound are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 9.04 (minor rotamer, br d, J = 10.4Hz, 0.37H), 8.68 (minor rotamer, d, J = 11.6 Hz, 0.39H), 8.37 (major rotamer, d, J = 1.6 Hz, 0.61H), 8.22 (major rotamer, br s, 0.56H), 7.59 (d, J = 9.2Hz, 1.20H), 7.22 (d, J = 8.8 Hz, 0.77H), 7.18-7.13 (m, 2.03H); 13C NMR (100MHz, Chloroform-d) δ major rotamer 163.0, 145.5, 135.5, 121.7, 119.9, 120.4(d, J = 253.3 Hz), minor rotamer 159.6, 146.3, 135.5, 122.5, 121.3, 120.4 (d,J = 253.3 Hz); 19 F NMR (377 MHz, Chloroform-d) δ -58.23 (major rotamer, s), -58.29 (minor rotamer, s)

[0056] Example 6:

[0057]

[0058] 1-Bromo-4-trimethylsilylbenzene (1f) was used instead of 4-bromoacetophenone (1a), otherwise the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a white solid (3f) (31 mg, 80%). The NMR data of this compound are as follows: 1 H NMR (600 MHz, Chloroform-d) δ 8.79 (s, 0.32H), 8.74 (d, J = 11.2Hz, 0.90H), 8.38 (s, 0.48H), 7.84 (d, J = 48.1 Hz, 0.45H), 7.55 (d, J = 7.0Hz, 1H), 7.49 (dd, J = 12.6, 8.3 Hz, 2H), 7.10 (d, J = 7.2 Hz, 1H), 0.26 (d,J = 9.9 Hz, 9H). 13 C NMR (151 MHz, Chloroform-d) δ 162.88, 159.44, 137.54, 137.37, 137.27, 136.83, 134.87, 134.27, 119.41, 118.01, -1.02, -1.04.

[0059] Example 7:

[0060]

[0061] Methyl 2-fluoro-4-bromobenzoate (1 g) was used instead of 4-bromoacetophenone (1a), otherwise the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a white solid (3 g) (32 mg, 81%). The NMR data of this compound are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 0.77H), 10.58 (d, J = 10.5 Hz, 0.28H), 8.99 (d, J = 10.5 Hz, 0.25H), 8.37 (s, 0.78H), 7.91 – 7.75 (m, 1H), 7.65 (dd, J = 13.5, 2.0 Hz, 0.78H), 7.36 (dd, J = 8.7, 2.0 Hz, 0.79H), 7.22 (dd, J = 13.1, 2.1 Hz, 0.27H), 7.07 (dd, J = 8.6, 2.1 Hz, 0.26H), 3.80 (s,3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.93 (d, J = 4.0 Hz), 161.01, 144.34 (d, J= 11.9 Hz), 133.21 (d, J = 2.2 Hz), 114.98 (d, J = 3.0 Hz), 112.94 (d, J =2.6 Hz), 107.23, 104.74, 52.51; 19 F NMR (564 MHz, Chloroform-d) δ -106.79, -107.02.

[0062] Example 8:

[0063]

[0064] N,N-dimethyl-4-bromobenzenesulfonamide (1h) was used instead of 4-bromoacetophenone (1a), otherwise the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a white solid (3h) (36.5 mg, 80%). The NMR data of this compound are as follows: 1H NMR (600 MHz, DMSO-d6) δ 9.77 (s, 0.81H), 9.67 (d, J = 10.7Hz, 0.26H), 8.11 (d, J = 10.7 Hz, 0.22H), 7.50 (s, 0.77H), 6.96 (d, J = 8.7Hz, 1.58H), 6.82 (dd, J = 20.3, 8.6 Hz, 2H), 6.56 (d, J = 8.7 Hz, 0.46H), 1.70 (s, 6H). 13 C NMR (151 MHz, DMSO-d6) δ 163.09, 160.75, 143.20, 142.63,129.74, 129.36, 129.25, 129.19, 119.49, 117.28, 38.02.

[0065] Example 9:

[0066]

[0067] 2-Bromofluorene (1i) was used instead of 4-bromoacetophenone (1a), otherwise the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give a yellow solid (3i) (31 mg, 73%). The NMR data of this compound are as follows: 1 H NMR(600 MHz, DMSO-d6) δ 10.28 (s, 0.73H), 10.24 (d, J = 10.9 Hz, 0.26H), 8.85(d, J = 10.9 Hz, 0.23H), 8.32 (d, J = 1.9 Hz, 0.71H), 7.93 (s, 0.72H), 7.81(t, J = 7.5 Hz, 2H), 7.59 – 7.50 (m, 1.68H), 7.43 (s, 0.25H), 7.35 (t, J =7.6 Hz, 1H), 7.27 (d, J = 7.4 Hz, 1H), 7.21 (d, J = 5.9 Hz, 0.25H), 3.89 (d,J = 7.6 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 162.99, 159.95, 144.96, 144.33,143.25, 143.05, 141.34, 141.22, 137.75, 137.73, 137.34, 137.14, 127.18,126.63, 125.46, 121.22, 120.69, 119.97, 119.94, 118.31, 116.87, 116.43,114.78, 36.93, 36.89。

Claims

1. A photochemical synthesis method for formamide compounds, characterized in that: Aryl halide 1a was dissolved in a solvent under a nitrogen atmosphere and reacted in a photoreactor in the presence of nickel catalyst, photocatalyst, base and formamide 2a. After the reaction was completed, the target product 3a was obtained by separation and purification. The reaction route is shown below: ； Wherein: R is selected from H, halogen, alkyl, alkoxy, aryl, sulfonamide, acyl, ester, aldehyde, trimethylsilyl, cyano; X is Cl, Br or I; The nickel catalyst is nickel acetate tetrahydrate, with 4,4'-di-tert-butyl-2,2'-dipyridine added as a ligand; The photocatalyst is thioxanone; The alkali is sodium bicarbonate; The solvent is ethyl acetate; The reaction wavelength is 395nm.

2. The photochemical synthesis method according to claim 1, characterized in that: The reaction time is 12-24 h.

3. The photochemical synthesis method according to claim 1, characterized in that: The separation and purification process involves adding water to the reaction solution, extracting with ethyl acetate, drying with anhydrous sodium sulfate, removing the solvent by rotary evaporation, and finally separating and purifying by column chromatography to obtain the target product.

4. The photochemical synthesis method according to claim 3, characterized in that: The eluent used in column chromatography separation and purification was petroleum ether: ethyl acetate = 5:1 ~ 1:1, v / v.

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