Photochemical synthesis method of formanilide compound

Abstract

The invention discloses a photochemical synthesis method of formanilide compounds, which comprises the following steps: by taking an aryl halide compound as a raw material, carrying out selective C-X bond formylation on the aryl halide compound in the presence of formamide, a catalyst and alkali to obtain the formanilide compounds with high selectivity. The method has the advantages of high efficiency, mild reaction conditions, convenience in operation, relatively short reaction time, relatively few byproducts and the like.

Description

Technical Field

[0001] The invention relates to a photochemical synthesis method of formanilide compounds, which belongs to the field of organic synthesis and involves selective formamidation of CX bonds of aryl halogen compounds to synthesize formanilide compounds. Background Art

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

[0003] The traditional method of synthesizing formanilide usually uses aniline and a formylation agent (such as formic acid, formic anhydride or formyl chloride). However, these methods have the following disadvantages: some methods need to be carried out at low temperature (usually below 0°C) and under anhydrous conditions, which increases the complexity of the operation; when using reagents such as phosphorus oxychloride, it is easy to decompose and may explode when in contact with water, and it is highly toxic, posing a health risk to operators; some formylation agents (such as N-(diethylaminoformyl)-N-methoxyformamide) are expensive, resulting in an increase in production costs; traditional methods may produce more by-products, reduce atomic utilization, and do not conform to the principles of green chemistry. Other methods for synthesizing formanilide compounds include reactions catalyzed by transition metals using formamide as a substrate, but these methods still have certain limitations, including the use of precious metals, the reaction conditions require high temperature and pressure, and strong acid and strong base 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 usually very mild, and the bond formation has high chemical selectivity and significant functional group tolerance. Xue and colleagues reported the photoinduced metal nickel-catalyzed CN coupling of aromatic chlorides. Although they were able to successfully construct primary and secondary amides with diverse structures, the reaction still required a high reaction temperature and increased energy consumption. Therefore, it is necessary to develop a method for preparing carboxylic anilide compounds with low raw materials, high atom economy, mild conditions and high yield. Summary of the invention

[0005] In view of the shortcomings of the existing synthesis routes, the present invention provides a photochemical synthesis method of formanilide compounds, which uses nickel and thioxanthone to synergistically catalyze the formamidation reaction of aromatic halides. The method has the advantages of easy availability of raw materials, simple process, mild conditions, high yield, wide substrate range, less by-products, etc.

[0006] The photochemical synthesis method of formanilide compounds of the present invention uses aryl halide as raw material, performs light irradiation reaction in the presence of nickel catalyst, photocatalyst, base and formamide, and obtains formanilide compounds after separation and purification.

[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 a substituent of the above groups; X is Cl, Br or I. The substituent includes conventional substitution modes such as heteroatom substitution and halogen substitution.

[0010] For example: R is H, chlorine, methyl, trifluoromethoxy, phenyl, acetyl, ester, aldehyde, trimethylsilyl, tert-butyl or cyano.

[0011] Specifically, the 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, the target product 3a is separated and purified.

[0012] The reaction route is as follows:

[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(diphenylphosphinopropane)nickel dichloride or nickel trifluoromethanesulfonate, and the added amount of the nickel catalyst is 5 mol%-50 mol% (calculated as aryl halide).

[0016] The photocatalyst is selected from thioxanthone, 4CzIPN, 4DPAIPN, tris(2-phenylpyridine)iridium or Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 The photocatalyst is prepared by using a photocatalyst such as a halogenated carbonyl group. The amount of the catalyst added is 1 mol%-20 mol% (calculated as aryl halide).

[0017] The base 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 the added amount is 1-3 times the equivalent (calculated as aryl halide).

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

[0019] The separation and purification is to add water to the reaction solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, finally remove the solvent by rotary evaporation, separate and purify by column chromatography, and the eluent during the column chromatography separation and purification is petroleum ether: ethyl acetate = 5:1 ~ 1:1, v / v, to obtain the target product.

[0020] The beneficial effects of the present invention are embodied 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, relatively few by-products, is compatible with a variety of functional groups, and is suitable for aryl halides with a variety of substituents. DETAILED DESCRIPTION

[0023] To further illustrate the features and advantages of the present invention, the technical solution of the present invention is described below in conjunction with specific embodiments. However, the following embodiments are only for further illustrating the present invention, rather than limiting the present invention.

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

[0025]

[0026]

[0027] For the above reaction, we used 4-bromoacetophenone (1a) and formamide (2a) as model substrates, Ni(OAc) 2 ·4H 2 O as a metal catalyst, 4,4'-di-tert-butyl-2,2'-bipyridine as a ligand, sodium bicarbonate as a base, and ethyl acetate as a solvent, and the synthesis of the target compound was achieved by screening different photocatalysts. Through the screening of different photocatalysts, benzophenone, 4CzIPN, 4DPAIPN, tris(2-phenylpyridine)iridium, Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 The target products were generated by photocatalysts such as thioxanthone or thioxanthone, among which thioxanthone was the photocatalyst with the best reaction effect.

[0028]

[0029]

[0030] After screening different photocatalysts, the metal nickel catalyst used in the reaction was screened. According to the experimental results, the target products were generated using nickel dichloride, nickel dibromide, nickel acetate tetrahydrate, 1,3-bis(diphenylphosphinopropane) nickel dichloride or nickel trifluoromethanesulfonate, among which nickel acetate tetrahydrate was the catalyst with the best reaction effect.

[0031]

[0032]

[0033] By screening different solvents, acetonitrile, acetone, dimethyl sulfoxide, ethyl formate and ethyl acetate can all produce the target product, among which ethyl acetate is 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. 2.0 times the equivalent of sodium bicarbonate can obtain 80% of the target product. For the reaction system, the use of organic bases has no obvious help to the reaction effect, the use of inorganic bases can obtain the target product, and the use of potassium salts and sodium salts can mostly achieve a reaction yield of more than 60%. In summary, after screening the base, the weak base sodium bicarbonate is the best in the reaction system, and a yield of 80% can be obtained.

[0037]

[0038]

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

[0040] The invention is further described below through specific embodiments.

[0041] Embodiment 1:

[0042]

[0043] In a 25 mL transparent Schlenk tube equipped with a magnetic stirrer, add the raw material 4-bromoacetophenone (1a) (0.2 mmol), formamide (2a) (0.5 mL), sodium bicarbonate (0.4 mmol), nickel catalyst Ni(OAc) 2 ·4H 2O (0.02 mmol, 10 mol%) and its ligand dtbpy (0.02 mmol, 10 mol%), thioxanthone photocatalyst (0.02 mmol, 10 mol%), 1.5 mL of ethyl acetate were added under nitrogen atmosphere. The reaction tube was fixed on a photoreactor with a wavelength of 395 nm. After reacting at room temperature for 12 h, it was extracted with water and ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated in vacuo. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a white solid (3a) (27 mg, 82%). The NMR data of the compound are: 1 H NMR (600 MHz, DMSO-d 6 ) 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-d 6 ) 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] Embodiment 2:

[0045]

[0046] Bromobenzene (1b) was used to replace 4-bromoacetophenone (1a), and the other steps were the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a yellow oil (3b) (16 mg, 66%). The NMR data of the compound are: 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] Embodiment 3:

[0048]

[0049] 4-bromoacetophenone (1a) was replaced by p-chlorobromobenzene (1c), and the other conditions were the same as those in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a white solid (3c) (23 mg, 72%). The NMR data of the compound are: 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] Embodiment 4:

[0051]

[0052] 4-Bromoacetophenone (1a) was replaced by p-cyanobenzene (1d), and the other conditions were the same as those in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid (3d) (23 mg, 78%). The NMR data of the compound are: 1 HNMR (600 MHz, DMSO-d 6 ) 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-d 6 ) 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] Embodiment 5:

[0054]

[0055] 4-(Trifluoromethoxy)bromobenzene (1e) was used to replace 4-bromoacetophenone (1a), and the other conditions were the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a yellow oil (3e) (30 mg, 73%). The NMR data of the compound are: 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] Embodiment 6:

[0057]

[0058] 1-Bromo-4-trimethylsilylbenzene (1f) was used to replace 4-bromoacetophenone (1a), and the other conditions were the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a white solid (3f) (31 mg, 80%). The NMR data of the compound are: 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] Embodiment 7:

[0060]

[0061] 2-Fluoro-4-bromobenzoic acid methyl ester (1 g) was used to replace 4-bromoacetophenone (1a), and the other conditions were the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a white solid (3 g) (32 mg, 81%). The NMR data of the compound are: 1 H NMR (400 MHz, DMSO-d 6 ) 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-d 6 ) 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] Embodiment 8:

[0063]

[0064] N,N-dimethyl-4-bromobenzenesulfonamide (1h) was used to replace 4-bromoacetophenone (1a), and the other conditions were the same as those in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a white solid (3h) (36.5 mg, 80%). The NMR data of the compound are: 1 H NMR (600 MHz, DMSO-d 6) 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-d 6 ) δ 163.09, 160.75, 143.20, 142.63,129.74, 129.36, 129.25, 129.19, 119.49, 117.28, 38.02.

[0065] Embodiment 9:

[0066]

[0067] 2-Bromofluorene (1i) was used to replace 4-bromoacetophenone (1a), and the other conditions were the same as in Example 1. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid (3i) (31 mg, 73%). The NMR data of the compound are: 1 H NMR (600 MHz, DMSO-d 6 ) 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). 13 C NMR (151 MHz, DMSO-d 6) 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 of formanilide compounds, characterized in that: Using aryl halide as raw material, light irradiation reaction is carried out in the presence of nickel catalyst, photocatalyst, base and formamide, and formanilide compounds are obtained after separation and purification; The structural formula of the aryl halide is: ； Wherein: R is selected from H, halogen, alkyl, alkoxy, aryl, sulfonamide, acyl, ester, aldehyde, trimethylsilyl, cyano, or a substituent of the above groups; X is Cl, Br or I.

2. The photochemical synthesis method according to claim 1, characterized in that: The 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, the target product 3a is separated and purified. The reaction route is as follows: 。 3. The photochemical synthesis method according to claim 2, characterized in that: The nickel catalyst is selected from nickel dichloride, nickel dibromide, nickel acetate tetrahydrate, 1,3-bis(diphenylphosphinopropane)nickel dichloride or trifluoromethanesulfonic acid, and the added amount of the nickel catalyst is 5 mol%-50 mol%.

4. The photochemical synthesis method according to claim 2, characterized in that: The photocatalyst is selected from thioxanthone, 4CzIPN, 4DPAIPN, tris(2-phenylpyridine)iridium or Ir[dF(CF3)ppy]2(dtbbpy)PF6 and the like, and the added amount of the catalyst is 1 mol%-20 mol%.

5. The photochemical synthesis method according to claim 2, characterized in that: The base 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 the added amount is 1-3 times the equivalent.

6. The photochemical synthesis method according to claim 2, characterized in that: The solvent is dimethyl sulfoxide, acetonitrile, ethyl formate, acetone, ethyl acetate or dibutyl ketone.

7. The photochemical synthesis method according to claim 2, characterized in that: The reaction wavelength is 365-425 nm and the reaction time is 12-24 h.

8. The photochemical synthesis method according to claim 2, characterized in that: The separation and purification is to add water to the reaction solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, finally remove the solvent by rotary evaporation, and separate and purify by column chromatography to obtain the target product.

9. The photochemical synthesis method according to claim 8, characterized in that: The eluent during column chromatography separation and purification is petroleum ether: ethyl acetate = 5:1 ~ 1:1, v / v.

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