Process for the synthesis of n-trifluoromethyl carboxamides from benzoyl isothiocyanates

Abstract

The application discloses a method for synthesizing N-trifluoromethyl secondary amide compounds from benzoyl isothiocyanate. The method is characterized in that silver fluoride is added in a sealed anhydrous and oxygen-free tube, and then argon is replaced for three times; under the ventilation condition, benzoyl isothiocyanate and triethylamine hydrogen trifluoride are added, anhydrous tetrahydrofuran is used as a reaction solvent, and sufficient reaction is carried out at 25-35 DEG C to obtain corresponding N-CF3 amide compounds. The method is simple and safe in process operation, high in reaction conversion rate, economical and practical in raw materials, low in waste and friendly to environment, and does not need to treat additional organic solvents. The introduction of trifluoromethyl in the synthesized N-trifluoromethyl secondary amide compounds is expected to change the physical properties and chemical properties of some drugs, and can increase the efficacy and application range of some amide drugs.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and relates to a method for synthesizing N-trifluoromethyl (N-CH3) secondary amide compounds from benzoyl isothiocyanate. BACKGROUND

[0002] Amides are important intermediates in organic synthesis, and the amide group has a special molecular structure and is widely used in the structural design of polymer materials. At the same time, amide drugs are closely related to our lives, and common ones are nicotinamide, pyrazinamide and lipoic acid, etc. In recent years, fluorine-containing organic compounds have attracted much attention due to their unique physicochemical properties and biological activities. Trifluoromethyl compounds are a typical class of fluorine-containing organic compounds and are widely used in the fields of medicine, pesticides and material science. N-trifluoromethyl amide compounds combining these two important structures naturally attract the attention of scientists. At present, there are some methods to obtain N-trifluoromethyl amide, but the synthesis of N-trifluoromethyl secondary amide has not been reported. However, the active structures of some drugs and organic intermediates are based on terminal amide groups, such as nicotinamide for treating dermatitis, pyrazinamide for treating tuberculosis, etc., so it is necessary to find a new method to study the terminal amide trifluoromethylation modification.

[0003]

[0004] Nicotinamide pyrazinamide

[0005] At present, some methods for directly preparing N-CF3 amides have been reported. Literature 1 (Scattolin T, Bouayad-Gervais S, Schoenebeck F. Straightforward access to N-trifluoromethyl amides, carbamates, thiocarbamates and ureas [J]. Nature, 2019, 573(7772): 102-107.) uses isothiocyanate, triphosgene and silver fluoride as raw materials to first synthesize N-CF3 carbamic fluoride, and then reacts with Grignard reagent to obtain N-CF3 amide. The synthesis route is shown below. However, since the Grignard reagent will affect the reactivity of the alkyl reagent, the introduction of functional groups to the carboxylic acid side of the amide (R1) is partially limited, and the method involving R1 as a hydrogen atom is not involved.

[0006]

[0007] Document 2 (Liu J, Parker M, Wang S, et al. Synthesis of N-trifluoromethylamides from carboxylic acids [J]. 2021.) reports a method for the direct conversion of readily available acyl halides (or active esters) to their corresponding N-CF3 amides via sequential fluorination and acylation of isothiocyanate, the key of which is the ligand 2,4,6-trimethylpyridine or pyridine, and the synthetic route is shown below. Similarly, this method does not involve reactions where R1 is hydrogen.

[0008] SUMMARY

[0009] The object of the present application is to provide a method for synthesizing N-trifluoromethyl (N-CH3) secondary amide compounds from benzoyl isothiocyanate.

[0010] The technical solution to achieve the object of the present application is:

[0011] The method for synthesizing N-trifluoromethyl secondary amide compounds from benzoyl isothiocyanate comprises the following steps:

[0012] In a sealed, anhydrous, and oxygen-free tube, add silver fluoride, then replace with argon three times, under aeration, add benzoyl isothiocyanate and triethylamine trifluoride, use anhydrous tetrahydrofuran as the reaction solvent, randomly tighten the bottle plug, and react at 25-35℃ for 6-8h. After the reaction is completed, filter, remove the reaction solvent by distillation under reduced pressure, and purify the reaction mixture by column chromatography to obtain the corresponding N-CF3 amide compound. The structural formula of the benzoyl isothiocyanate is The structural formula of the corresponding N-CF3 amide compound is R is H, 2-methyl, 3-methyl, or 4-methyl.

[0013] Preferably, the molar ratio of benzoyl isothiocyanate, silver fluoride, and triethylamine trifluoride is 1:2.4:1.

[0014] Preferably, the amount of anhydrous tetrahydrofuran used is 5.0mL / 2mmol of benzoyl isothiocyanate.

[0015] Compared with the prior art, the present application has the following significant advantages:

[0016] (1) The present application first synthesizes N-trifluoromethyl secondary amide compounds, and the target product can be obtained in one step with a relatively high yield.

[0017] (2) The introduction of trifluoromethyl in the N-trifluoromethyl secondary amide compound of the present application is expected to change the physical and chemical properties of some drugs, possibly increasing the efficacy and application range of some amide drugs, and also possibly obtaining N-CF3-containing secondary amide polymers to change the performance of existing materials. DETAILED DESCRIPTION

[0018] The present application will be further described in detail below with specific examples.

[0019] The method for synthesizing N-trifluoromethyl secondary amide compounds from benzoyl isothiocyanate of the present application has the following synthesis route:

[0020]

[0021] Among them, is:

[0022]

[0023] The synthesis mechanism is:

[0024]

[0025] The carbon-sulfur double bond in benzoyl isothiocyanate will undergo desulfurization and fluorination under the action of silver fluoride to generate an unstable N=CF2 intermediate. This intermediate can undergo addition reaction with fluorine released by a hydrogen fluoride reagent (triethylamine trifluoride) to obtain the final product.

[0026] Example 1

[0027] First, a solid reagent, silver fluoride (610 mg, 4.8 mmol), was added to a sealed 35 mL anhydrous and oxygen-free tube (Schlenk tube), followed by three times of argon replacement. Under the condition of ventilation, benzoyl isothiocyanate (326 mg, 2 mmol) and triethylamine trifluoride (322 mg, 2 mmol) were added, 5 mL of anhydrous tetrahydrofuran was used as the reaction solvent, the bottle cap was randomly tightened, and the reaction was carried out at 25°C for 6 h. After the reaction was completed, the filtrate was obtained by filtering with a sand core funnel, the reaction solvent was removed by distillation under reduced pressure, and the reaction mixture was purified by silica gel flash chromatography to obtain the corresponding N-CF3 benzamide The yield was 82%.

[0028] 1 H NMR (500 MHz, Chloroform-d) δ 8.85 (s, 1H), 7.83 (d, J = 7.8 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 7.7 Hz, 2H).

[0029] 13C NMR (126 MHz, Chloroform-d) δ 166.34, 133.24, 131.35, 128.70, 127.67, 120.35, 118.27.

[0030] Example 2

[0031] First, a solid reagent, silver fluoride (610 mg, 4.8 mmol), was added to a sealed 35 mL anhydrous oxygen-free tube (Schlenk tube), followed by three times of argon replacement. Under the ventilation state, 2-methylbenzoylisothiocyanate (354 mg, 2 mmol) and triethylamine trifluoride (322 mg, 2 mmol) were added, 5 mL of anhydrous tetrahydrofuran was used as the reaction solvent, the bottle plug was randomly tightened, and the reaction was carried out at 25°C for 6 h. After the reaction was completed, the filtrate was obtained by filtering with a sand core funnel, the reaction solvent was removed by distillation under reduced pressure, and the reaction mixture was purified by silica gel flash chromatography to obtain the corresponding N-CF3 benzamide The yield was 68%.

[0032] 1 H NMR (500 MHz, Chloroform-d) δ 7.55 (s, 1H), 7.42-7.34 (m, 2H), 7.26-7.17 (m, 2H), 2.42 (s, 3H).

[0033] 13 C NMR (126 MHz, Chloroform-d) δ 166.91, 137.14, 132.12, 131.26, 131.23, 126.51, 125.53, 119.40, 117.32, 19.42.

[0034] Example 3

[0035] First, a solid reagent, silver fluoride (610 mg, 4.8 mmol), was added to a sealed 35 mL anhydrous oxygen-free tube (Schlenk tube), followed by three times of argon replacement. Under the ventilation state, 2-methylbenzoylisothiocyanate (354 mg, 2 mmol) and triethylamine trifluoride (322 mg, 2 mmol) were added, 5 mL of anhydrous tetrahydrofuran was used as the reaction solvent, the bottle plug was randomly tightened, and the reaction was carried out at 25°C for 6 h. After the reaction was completed, the filtrate was obtained by filtering with a sand core funnel, the reaction solvent was removed by distillation under reduced pressure, and the reaction mixture was purified by silica gel flash chromatography to obtain the corresponding N-CF3 benzamide The yield was 70%.

[0036] 1H NMR (500 MHz, Chloroform-d) δ 7.90 (s, 1H), 7.65 - 7.55 (m, 2H), 7.39 (d, J = 7.7 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 2.38 (s, 3H).

[0037] 13 C NMR (126 MHz, Chloroform-d) δ 165.12, 138.57, 133.73, 131.03, 128.38, 127.78, 124.13, 119.85, 117.77, 20.82.

[0038] Example 4

[0039] First, a solid reagent, silver fluoride (610 mg, 4.8 mmol) was added to a sealed 35 mL anhydrous oxygen-free tube (Schlenk tube), followed by three times of argon replacement, under the condition of ventilation, 4-methylbenzoylisothiocyanate (354 mg, 2 mmol) and triethylamine trifluoride (322 mg, 2 mmol) were added, 5 mL of anhydrous tetrahydrofuran was used as the reaction solvent, the bottle cap was randomly tightened, and the reaction was carried out at 25°C for 6 h. After the reaction was completed, the filtrate was obtained by filtering with a sand core funnel, the reaction solvent was removed by distillation under reduced pressure, and the reaction mixture was purified by silica gel flash chromatography to obtain the corresponding N-CF3 benzamide The yield was 75%.

[0040] 1 H NMR (500 MHz, Chloroform-d) δ 7.95 (s, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H), 2.41 (s, 3H).

[0041] 13 C NMR (126 MHz, Chloroform-d) δ 164.93, 143.88, 129.18, 128.20, 127.20, 119.92, 117.84, 21.19.

[0042] Comparative Example 1

[0043] This comparative example is basically the same as Example 1, the only difference is that acetonitrile is used as the solvent, and basically no product is generated.

[0044] Comparative Example 2

[0045] This comparative example is basically the same as Example 1, the only difference is that n-hexane is used as the solvent, and the yield is only 15%.

Claims

1. Process for the synthesis of N-trifluoromethyl secondary amide compounds from benzoylisothiocyanates, characterized in that, comprising the steps of: In a sealed, anhydrous and anaerobic tube, silver fluoride is added, followed by three times of argon replacement. Under aeration, benzoyl isothiocyanate and triethylamine trifluoride are added, anhydrous tetrahydrofuran is used as a reaction solvent, the bottle cap is immediately tightened, and the reaction is carried out at 25-35°C for 6-8h. After the reaction is completed, filtration is performed, the reaction solvent is removed by distillation under reduced pressure, and the reaction mixture is separated and purified by column chromatography to obtain a corresponding N-CF3 amide compound, and the structural formula of the benzoyl isothiocyanate is The structural formula of the corresponding N-CF3 amide compound is R is H, 2-methyl, 3-methyl or 4-methyl.

2. The method of claim 1, wherein, The molar ratio of benzoyl isothiocyanate, silver fluoride and triethylamine trifluoride is 1:2.4:

1.

3. The method of claim 1, wherein, The amount of anhydrous tetrahydrofuran is 5.0 mL per 2 mmol of benzoyl isothiocyanate.

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