Preparation method of primary amide compound
Through the reaction of hydroxamic acid and thiourea dioxide in organic solvents, the problems of high toxicity and inconvenience in the preparation methods of existing primary amide compounds have been solved, and efficient and green primary amide compounds are achieved, with strong functional group compatibility, wide substrate range and high product yield.
Patent Information
- Application Number
- CN202510303147.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-14
- Publication Date
- 2025-06-17
AI Technical Summary
The existing preparation methods for primary amide compounds have problems such as high toxicity of reagents, inconvenient preparation, expensive and sensitive catalysts, and limited substrate range.
Hydroxyl group activation and N-O bond reduction and cleavage reactions were performed in an organic solvent using hydroxamic acid and thiourea dioxide (TDO) to obtain primary amide compounds. The process includes mixing hydroxamic acid with TDO and an organic solvent, stirring at 20-150°C, and subsequently performing separation and purification to obtain a primary amide compound.
It has achieved efficient preparation of primary amide compounds, strong functional group compatibility, wide substrate range, high product yield, and simple raw materials acquisition, easy operation and green reaction.
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Figure CN120157555A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for preparing primary amide compounds. Background Art
[0002] Amides are one of the widely used intermediates in the production of fine chemicals, polymers and materials. Primary amides containing free amino groups are considered to be an important class of synthetic and pharmaceutical intermediates and are widely present in the preparation of N-substituted amide compounds.
[0003] In synthetic organic chemistry, it is necessary to develop a method for preparing primary amide compounds with inexpensive, green and simple operation. Traditional methods for synthesizing primary amides include Schmidt reaction, hydration of nitrile compounds and amidation of carbonyl compounds. In recent years, transition metal catalysis strategies, such as direct amidation of aldehydes and alcohols, catalytic hydration of organic nitriles and reverse amidation of amides, have been reported successively. However, these methods usually face problems such as harsh reaction conditions, poor functional group tolerance, and contamination of catalysts and additives.
[0004] Hydroxamic acids and their derivatives have obvious reductive N-O bond cleavage reactivity and are widely used in the synthesis of primary amide compounds. Using stoichiometric metal-based reducing agents such as Cu(II) ions, TiCl3, Mo(CO)6, Li, and Zn is one of the most representative strategies to promote N-O bond cleavage to obtain primary amides. In addition, strategies such as transfer hydrogenation and ruthenium-catalyzed reductive N-O bond cleavage of N-oxy-substituted amides have been proven feasible. In 2024, the research team of Professor Jongwoo Son from Dong-A University in South Korea developed a copper-catalyzed method for preparing primary amides from dioxazolone using silane [H. Bae, J. Park, R. Yoon, S. Lee, J. Son, RSC Adv., 2024, 14, 9440-9444.]. In addition, several recent works have disclosed the feasibility of sulfur-containing compounds mediating the conversion of N-alkoxyamides to primary amides. In 2019, Professor Yunfei Du and his colleagues from Tianjin University treated N-alkoxybenzamides with S8 and DABCO in DMSO, effectively providing various primary amides with good functional tolerance [S. Wang, X. Zhao, D. Zhang-Negrerie, Y. Du, Org. Chem. Front., 2019, 6, 347-351.]. The research team of Professor Yuanzhi Xia from Wenzhou University reported that the use of thioacetic acid and NH4HCO3 in ethanol can promote the N-O bond cleavage of hydroxamic acids to obtain primary amides [R. S. Wang, Y. F. Chen, B. J. Fei, J. H. Hu, J. H. Chen, Y. S. Luo, Y. Z. Xia, Org. Lett., 2023, 25, 2970-2974.]. However, many methods still have problems such as high reagent toxicity, inconvenient preparation, expensive and sensitive catalysts, and limited substrate scope.
[0005] Thiourea dioxide (TDO) is widely known as a "green industrial reducing agent" and has extensive applications in the fields of chemistry, biology, textiles, and the paper industry. Recently, TDO has been proven to be applicable to organic synthesis fields such as organic catalysis, polymerization, and phase transfer reactions. In 2024, the research team of Professor Song reported that TDO can be used as a hydroxyl activator to effectively convert aldoximes to nitriles [P. D. Song, Z. Cui, T. T. Meng, H. J. Rong, M. Z. Mao, C. F. Yang, Asian J. Org. Chem., 2024, 13, e202400291.]. Given the bifunctionality of TDO - electrophilicity and reducibility, we propose a method for obtaining primary amide compounds by hydroxyl activation and N-O bond reductive cleavage of hydroxamic acids with TDO. Summary of the Invention
[0006] Aiming at the existing technical problems, the purpose of the present invention is to provide a preparation method of primary amide compounds with simple raw material acquisition, easy operation, high functional group compatibility and high yield.
[0007] To achieve the above invention purpose, the present invention adopts the following technical solutions:
[0008] The present invention provides a preparation method of primary amide compounds shown in formula II, specifically including the following steps:
[0009] First, mix the hydroxamic acid shown in formula I with thiourea dioxide (TDO) and an organic solvent, and then fully stir and react at 20 - 150 °C. After the reaction is complete, separate and purify the obtained reaction mixture to obtain the primary amide compound shown in formula II;
[0010]
[0011] Among them, R is phenyl, naphthyl, furyl, thienyl, pyridyl, C1 - C6 alkyl, phenyl - substituted C1 - C4 alkyl or phenyl - substituted C2 - C4 alkenyl, and the phenyl, naphthyl, furyl, thienyl, pyridyl are each independently unsubstituted or substituted by 1 or more substituents, and each substituent is independently selected from phenyl, halogen, trifluoromethyl, cyano, nitro or C1 - C4 alkyl.
[0012] Preferably, the molar ratio of the hydroxamic acid to thiourea dioxide in the feed is 1:0.5 - 3, and more preferably 1:2.
[0013] Preferably, the organic solvent is DMAc, DMF, DCE, Dioxane, Toluene, MeCN, EtOH or H2O, and more preferably DMAc.
[0014] Preferably, in the reaction system, the feeding concentration of the hydroxamic acid is 0.1 - 1.0 M, and more preferably 0.5 M.
[0015] Preferably, the stirring temperature is 100 - 150 °C, and more preferably 120 °C; the stirring time is 4 - 7 h, and more preferably 5 h.
[0016] Preferably, the reaction atmosphere of the reaction is air, N2 or O2, and most preferably air.
[0017] Preferably, the separation and purification specifically comprises the following steps: extracting the obtained reaction mixture with a solvent, washing with water, drying with anhydrous sodium sulfate, and removing the organic solvent by rotary evaporation to obtain a crude primary amide product; purifying the crude product with a silica gel column, and removing the organic solvent by rotary evaporation to obtain a solid, which is a primary amide compound. It is further preferred that the solvent used for the extraction is ethyl acetate or DMF. It is further preferred that the developing solvent used for the silica gel column purification is petroleum ether / ethyl acetate, methanol / dichloromethane, and it is further preferred that petroleum ether / ethyl acetate.
[0018] The hydroxamic acid compound of the present invention can be prepared according to the method reported in the existing literature, for example, according to the literature [GF Zhang, Y. Cui, YY Zhao, YQ Cui, SX Bao, CRDing, Chemistry Select 2020, 5, 7817-7821.], the specific method for preparing the hydroxamic acid compound is: first, hydroxylamine hydrochloride and inorganic base are dissolved in a solvent according to a certain feed ratio, and stirred in an ice-water bath for 0-5 hours; an acyl chloride compound dissolved in an organic solvent is added, and stirred at room temperature for 0-24 hours. Extract with an organic solvent, dry with anhydrous sodium sulfate, and remove the organic solvent by rotary evaporation to obtain a solid, which is a hydroxamic acid compound. The inorganic base is sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, and more preferably potassium carbonate. The molar ratio of the feed of hydroxylamine hydrochloride and the inorganic base is preferably 1:0.5-3, and more preferably 1:1. The stirring reaction time under the ice-water bath is preferably 0.5 hours. The organic solvent for dissolving the acyl chloride compound is preferably ethyl acetate, ethanol, dichloromethane or toluene, and more preferably ethyl acetate. The stirring reaction time at room temperature is preferably 12 hours. The extraction solvent is preferably ethyl acetate, ethanol, dichloromethane, toluene, and more preferably ethyl acetate.
[0019] Compared with the existing technology, the present invention has the following beneficial effects:
[0020] 1) The preparation method of the primary amide compounds provided by the present invention has strong functional group compatibility, a wide substrate range and a high product yield.
[0021] 2) As a commercial reagent, TDO was used as a bifunctional reagent for the first time, with simple raw material sources, convenient operation and green reaction. BRIEF DESCRIPTION OF THE DRAWINGS
[0022] Figures 1 - 28 The products prepared in Example 1 to Example 28 are 1 HNMR spectrum. DETAILED DESCRIPTION
[0023] The present invention will be described below with specific embodiments. It should be noted that the embodiments are only used to further illustrate the present invention, but should not be construed as limiting the protection scope of the present invention. The present invention is not limited in any form, and those skilled in the art can make some non-essential improvements and adjustments based on the content of the above invention.
[0024] Example 1
[0025] Preparation of benzohydroxamic acid: Hydroxylamine hydrochloride (1.39 g, 20.0 mmol, 2.0 eq.), ethyl acetate (60 mL), H2O (30 mL) and K2CO3 (2.76 g, 20.00 mmol, 2.0 eq) were added to a 250 mL flask at 0 °C for 0.5 h. Then benzoyl chloride (10.0 mmol, 1.0 eq.) dissolved in 20 mL of ethyl acetate was added dropwise to the reaction mixture. The solution was heated to room temperature and stirred for 12 h. Thereafter, the resulting mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate, and the product was washed with diethyl ether to obtain a white solid, namely benzohydroxamic acid. The 1H NMR of benzohydroxamic acid is shown in 1 1H NMR is shown in Figure 1 。
[0026] Example 2
[0027] Preparation of benzamide: Benzohydroxamic acid (68.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Thereafter, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, namely benzamide, with a yield of 96%. The 1H NMR of benzamide is shown in 1 1H NMR is shown in Figure 2 。
[0028] Example 3
[0029] Preparation of p-methylbenzamide: p-Methylbenzohydroxamic acid (75.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Thereafter, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was p-methylbenzamide, with a yield of 95%. The 1 1H NMR is shown in Figure 3 .
[0030] Example 4
[0031] Preparation of p-methoxybenzamide: p-Methoxybenzohydroxamic acid (83.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Thereafter, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was p-methoxybenzamide, with a yield of 95%. The 1 1H NMR is shown in Figure 4 .
[0032] Example 5
[0033] Preparation of p-tert-butylbenzamide: p-Methoxybenzohydroxamic acid (96.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Thereafter, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was p-tert-butylbenzamide, with a yield of 98%. The 1 1H NMR is shown in Figure 5 .
[0034] Example 6
[0035] Preparation of p-phenylbenzamide: p-Methoxybenzohydroxamic acid (106.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Thereafter, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was p-phenylbenzamide, with a yield of 87%. The 1 1H NMR is shown in Figure 6 .
[0036] Example 7
[0037] Preparation of p-fluorobenzamide: p-Fluorobenzohydroxamic acid (77.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Thereafter, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was p-fluorobenzamide, with a yield of 91%. The 1 1H NMR is shown in Figure 7 .
[0038] Example 8
[0039] Preparation of p-chlorobenzamide: p-Chlorobenzohydroxamic acid (85.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Thereafter, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was p-chlorobenzamide, with a yield of 93%. The 1 1H NMR is shown in Figure 8 .
[0040] Example 9
[0041] Preparation of p-bromobenzamide: p-Bromobenzhydroxamic acid (108 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Then, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was p-bromobenzamide, with a yield of 90%. The 1 1H NMR is shown in Figure 9 .
[0042] Example 10
[0043] Preparation of p-iodobenzamide: p-Iodobenzhydroxamic acid (131.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Then, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was p-iodobenzamide, with a yield of 85%. The 1 1H NMR is shown in Figure 10 .
[0044] Example 11
[0045] Preparation of p-(trifluoromethyl)benzamide: p-(Trifluoromethyl)benzhydroxamic acid (102.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Then, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was p-(trifluoromethyl)benzamide, with a yield of 89%. The 1 1H NMR is shown in Figure 11 .
[0046] Example 12
[0047] Preparation of p-cyanobenzamide: p-Cyanobenzhydroxamic acid (81 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Thereafter, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was p-cyanobenzamide, with a yield of 91%. The 1 1H NMR is shown in Figure 12 .
[0048] Example 13
[0049] Preparation of p-nitrobenzamide: p-Nitrobenzhydroxamic acid (91 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Thereafter, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was p-nitrobenzamide, with a yield of 81%. The 1 1H NMR is shown in Figure 13 .
[0050] Example 14
[0051] Preparation of m-methylbenzamide: m-Methylbenzhydroxamic acid (75.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Thereafter, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was m-methylbenzamide, with a yield of 87%. The 1 1H NMR is shown in Figure 14 .
[0052] Example 15
[0053] Preparation of m-nitrobenzamide: m-Nitrobenzhydroxamic acid (91 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Thereafter, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was m-nitrobenzamide, with a yield of 86%. The 1 1H NMR is shown in Figure 15 .
[0054] Example 16
[0055] Preparation of m-chlorobenzamide: m-Chlorobenzhydroxamic acid (85.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Thereafter, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was m-chlorobenzamide, with a yield of 82%. The 1 1H NMR is shown in Figure 16 .
[0056] Example 17
[0057] Preparation of o-methylbenzamide: o-Methylbenzhydroxamic acid (75.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Thereafter, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was o-methylbenzamide, with a yield of 78%. The 1 1H NMR is shown in Figure 17 .
[0058] Example 18
[0059] Preparation of o-chlorobenzamide: o-Chlorobenzhydroxamic acid (85.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Thereafter, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether as the eluent) to obtain a white solid, which was o-chlorobenzamide, with a yield of 72%. The 1 1H NMR is shown in Figure 18 .
[0060] Example 19
[0061] Preparation of o-nitrobenzamide: o-Nitrobenzhydroxamic acid (91 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Thereafter, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was o-nitrobenzamide, with a yield of 76%. The 1 1H NMR is shown in Figure 19 .
[0062] Example 20
[0063] Preparation of 3,4-dichlorobenzamide: 3,4-Dichlorobenzhydroxamic acid (102 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Thereafter, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was 3,4-dichlorobenzamide, with a yield of 83%. The 1 1H NMR is shown in Figure 20 .
[0064] Example 21
[0065] Preparation of 1-naphthalenecarboxamide: 1-Naphthalenecarboxylic hydroxamic acid (93.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Thereafter, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was 1-naphthalenecarboxamide, with a yield of 77%. The 1 1H NMR is shown in Figure 21 .
[0066] Example 22
[0067] Preparation of 2-naphthalenecarboxamide: 2-Naphthalenecarboxylic hydroxamic acid (93.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Thereafter, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was 2-naphthalenecarboxamide, with a yield of 88%. The 1 1H NMR is shown in Figure 22 .
[0068] Example 23
[0069] Preparation of pyridinecarboxamide: Pyridinecarboxylic hydroxamic acid (69.0 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 h. Thereafter, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether as the eluent) to obtain a white solid, which was pyridinecarboxamide, with a yield of 86%. The 1 1H NMR is shown in Figure 23 .
[0070] Example 24
[0071] Preparation of furanformamide: Furan hydroxamic acid (63.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 hours. Then, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was furanformamide, with a yield of 88%. The 1 1H NMR is shown in Figure 24 .
[0072] Example 25
[0073] Preparation of thiopheneformamide: Thiophene hydroxamic acid (71.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 hours. Then, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was thiopheneformamide, with a yield of 93%. The 1 1H NMR is shown in Figure 25 .
[0074] Example 26
[0075] Preparation of cinnamamide: N-Hydroxycinnamamide (81.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 hours. Then, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was cinnamamide, with a yield of 85%. The 1 1H NMR is shown in Figure 26 .
[0076] Example 27
[0077] Preparation of 3-phenylpropanamide: 3-phenylpropanohydroxamic acid (71.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 hours. Then, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether as the eluent) to obtain a white solid, which was 3-phenylpropanamide, with a yield of 73%. The 1 1H NMR is shown in Figure 27 .
[0078] Example 28
[0079] Preparation of trimethylformamide: Trimethylmethanohydroxamic acid (58.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 hours. Then, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether as the eluent) to obtain a white solid, which was trimethylformamide, with a yield of 77%. The 1 1H NMR is shown in Figure 28 .
[0080] Example 29
[0081] Different feeding ratios: Benzohydroxamic acid (68.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.5 mmol, 3.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 hours. Then, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was benzamide, with a yield of 77%.
[0082] Example 30
[0083] Different solvents: Benzohydroxamic acid (68.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMF (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 hours. Then, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was benzamide, with a yield of 81%.
[0084] Example 31
[0085] Different solvent concentrations: Benzohydroxamic acid (68.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (0.5 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 5 hours. Then, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was benzamide, with a yield of 63%.
[0086] Example 32
[0087] Different reaction temperatures: Benzohydroxamic acid (68.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 100 °C and stirred for 5 hours. Then, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was benzamide, with a yield of 82%.
[0088] Example 33
[0089] Different reaction times: Benzohydroxamic acid (68.5 mg, 0.5 mmol, 1.0 eq.), TDO (108 mg, 1.0 mmol, 2.0 eq.) and DMAc (1 mL) were added to a 15 mL flask. The solution was heated to 120 °C and stirred for 7 hours. Then, the resulting mixture was extracted with ethyl acetate, washed with H2O, and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to remove ethyl acetate. The crude product was further purified by silica gel column chromatography (using ethyl acetate / petroleum ether = 1:2 as the eluent) to obtain a white solid, which was benzamide, with a yield of 94%.
Claims
1. A method for preparing a primary amide compound represented by formula II, characterized in that: The preparation method specifically comprises the following steps: First, the hydroxamic acid of formula I is mixed with thiourea dioxide and an organic solvent, and then stirred at 20-150° C. to react. After the reaction is complete, the obtained reaction mixture is separated and purified to obtain a primary amide compound of formula II; wherein thiourea dioxide is TDO; in, R is phenyl, naphthyl, furanyl, thienyl, pyridyl, C1-C6 alkyl, C1-C4 alkyl substituted by phenyl or C2-C4 alkenyl substituted by phenyl, and the phenyl, naphthyl, furanyl, thienyl and pyridyl are each independently unsubstituted or substituted by one or more substituents, each of which is independently selected from phenyl, halogen, trifluoromethyl, cyano, nitro or C1-C4 alkyl.
2. The preparation method according to claim 1, characterized in that: The molar ratio of the hydroxamic acid to thiourea dioxide is 1:0.5-3.
3. The preparation method according to claim 2, characterized in that: The molar ratio of the hydroxamic acid to thiourea dioxide is 1:
2.
4. The preparation method according to claim 1, characterized in that: The organic solvent is DMAc, DMF, DCE, Dioxane, Toluene, MeCN, EtOH or H2O.
5. The preparation method according to claim 1, characterized in that: In the reaction system, the feed concentration of the hydroxamic acid is 0.1-1.0M.
6. The preparation method according to claim 5, characterized in that: In the reaction system, the feed concentration of the hydroxamic acid is 0.5M.
7. The preparation method according to claim 1, characterized in that: The stirring temperature is 100-150°C; the stirring time is 4-7h.
8. The preparation method according to claim 7, characterized in that: The stirring temperature was 120°C and the stirring time was 5 h.
9. The preparation method according to claim 1, characterized in that: The reaction atmosphere of the reaction is air, N2 or O2.