Synthesis method of N-substituted aromatic formamide based on 2,2,2-trifluoroaryl ethanone
Patent Information
- Application Number
- GB2023005876
- Authority / Receiving Office
- GB · GB
- Patent Type
- Patents
- Current Assignee / Owner
- Filing Date
- 2023-04-21
- Publication Date
- 2025-07-09
- Estimated Expiration
- 2043-04-21
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Abstract
Description
[0001] The present disclosure relates to the technical field of organic chemistry, particularly to a synthesis method of N-substituted aromatic formamide based on 2,2,2-trifluoroaryl ethanone. BACKGROUND
[0002] Amines are a class of important compounds, and have wide applications. For example, more than 25% of drug molecules contain amide bonds, among them, penicillin drugs are the most famous (Tetrahedron 2005, 61(46), 10827-10852). In addition, pesticides and herbicides that are widely used in agriculture also generally contain amide bonds (Macromolecules 2018, 51(5), 1769-1776). Since the amide-amide hydrogen bond can effectively improve mechanical property, amide is also widely used in polymer nano composites (ACS Applied Polymer Materials 2020, 2(7), 2934-2945).
[0003] The traditional methods for synthesizing amine compounds are that carboxylic acid and its derivatives are condensed with amine. However, in this method, it is usually needed to activate carboxylic acid followed by reacting, so reaction conditions are harsh, and it is often needed to use an equivalent amount of activating reagents or coupling reagents. In addition, there are also reports on methods for the synthesis of amides using carboxylic acid and phenylisothiocyanate under mild conditions (Chin. J. Org. Chem. 2018, 38(7), 1740-1748). However, such the methods are expansive in raw materials and cause the discharge of sulfides.
[0004] In view of the above factors, a simple and efficient amide synthesis method with mild reaction conditions is particularly developed, which has high theoretical and practical application values. SUMMARY
[0005] The objective of the present disclosure is to provide a synthesis method of N-substituted aromatic formamide based on 2,2,2-trifluoroaryl ethanone to solve the problems proposed in the above background.
[0006] The objective of the present disclosure is achieved by the following technical solution: provided is a synthesis method of N-substituted aromatic formamide based on 2,2,2-trifluoroaryl ethanone, in which N-substituted aromatic formamide is prepared in a reaction solvent in the presence of an alkali by using amine and a 2,2,2-trifluoroaryl ethanone reagent as raw materials, and the reaction process is as follows: O R-NH2 K2CO3 DMSO, 60°C
[0007] where, Ar is substituted phenyl, and R is alkyl or substituted phenyl;
[0008] The synthesis method specifically includes the following operation steps:
[0009] in an air atmosphere, magnetically mixing 0.1-0.5 mmol of amine with 0.2-1 mmol of 2,2,2-trifluoroaryl ethanone and 0.1-1 mmol of potassium carbonate for 2-4 h at 40-60°C in dimethyl sulfoxide (DMSO), monitoring via thin-layer chromatography (TLC) during the reaction until the completion of the reaction, posttreating, adding a proper amount of ethyl acetate for extraction, drying with absolute sodium sulfate, spin drying a solvent under reduced pressure, and then separating via column chromatography to obtain purified N-substituted aromatic formamide.
[0010] Provided is a synthesis method of N-substituted aromatic formamide based on 2,2,2-trifluoroaryl ethanone, the synthesis method specifically includes the following operation steps:
[0011] in an air atmosphere, magnetically mixing 0.2 mmol of amine with 0.3 mmol of 2,2,2-trifluoroaryl ethanone and 0.4 mmol of potassium carbonate for 4 h at 60°C in DMSO, monitoring via TLC during the reaction until the completion of the reaction, posttreating, adding a proper amount of ethyl acetate for extraction, drying with absolute sodium sulfate, spin drying a solvent under reduced pressure, and then separating via column chromatography to obtain purified N-substituted aromatic formamide.
[0012] Further, the amine comprises any one of aniline, p-toluidine and ethylamine.
[0013] Further, the 2,2,2-trifluoroaryl ethanone reagent comprises any one of 2,2,2-trifluoroaryl ethanone and 4-(trifluoroacetyl)toluene.
[0014] Further, the reaction solvent is DMSO.
[0015] Further, the alkali is potassium carbonate.
[0016] Provided is a synthesis method of N-substituted aromatic formamide based on 2,2,2-trifluoroaryl ethanone, the synthesis method includes the following steps:
[0017] in an air atmosphere, magnetically mixing 0.2 mmol of aniline with 0.3 mmol of 2,2,2-trifluoroaryl ethanone and 0.4 mmol of potassium carbonate for 4 h at 60°C in DMSO, monitoring via TLC during the reaction until the completion of the reaction, posttreating, adding a proper amount of ethyl acetate for extraction, drying with absolute sodium sulfate, spin drying a solvent under reduced pressure, and then separating via column chromatography to obtain purified N-phenyl benzamide.
[0018] The present disclosure is realized as follows: a synthesis method of N-substituted aromatic formamide includes the steps: performing coupling reaction for 4 hours under the alkaline condition with 2,2,2-trifluoroaryl ethanone as a reaction substrate so as to prepare N-substituted aromatic formamide in a high yield.
[0019] Compared with the prior art, the present disclosure has the beneficial effects:
[0020] the simple method for preparing N-substituted aromatic formamide of the present disclosure avoids use of complicated raw materials and multi-step reaction;
[0021] due to use of amine and 2,2,2-trifluoroaryl ethanone, the present disclosure is simple and available in raw materials, and suitable for synthesis of multiple N-substituted aromatic formamide compounds;
[0022] the method of the present disclosure is efficient in reaction, simple to operate, low in cost, less in side products and high in product purity;
[0023] the product molecule prepared by the method of the present disclosure has amide bonds which are widely present in multiple drug molecules, and therefore the obtained product has considerable application prospect.
[0024] In the present disclosure, N-substituted aromatic formamide is simply and efficiently synthesized by using amine and 2,2,2-trifluoroaryl ethanone as raw materials. This reaction is simple and available in raw materials, convenient to operate and high in yield. BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1: H nuclear magnetic resonance spectra of compound la.
[0026] FIG. 2: C nuclear magnetic resonance spectra of compound la. DETAILED DESCRIPTION OF THE EMBODIMENTS
[0027] Next, the technical solution in embodiments of the present disclosure will be clearly and completely described in combination with embodiments of the present disclosure. Obviously, the described embodiments are only some embodiments but not all the embodiments. Based on the embodiments of the present disclosure, other embodiments obtained by persons of ordinary skill in the art without creative efforts are all included within the scope of protection of the present disclosure.
[0028] As shown in FIGs.1-2, in a synthesis method of N-substituted aromatic formamide based on 2,2,2-trifluoroaryl ethanone, N-substituted aromatic formamide is prepared in a reaction solvent in the presence of an alkali by using amine and a 2,2,2-trifluoroaryl ethanone reagent as raw materials, and the reaction process is as follows: H
[0029] where, Ar is substituted phenyl, and R is alkyl or substituted phenyl;
[0030] the synthesis method specifically comprises the following operation steps:
[0031] in an air atmosphere, magnetically mixing 0.1-0.5 mmol of amine with 0.2-1 mmol of 2,2,2-trifluoroaryl ethanone and 0.1-1 mmol of potassium carbonate for 2-4 h at 40-60°C in DMSO, monitoring via TLC during the reaction until the completion of the reaction, posttreating, adding a proper amount of ethyl acetate for extraction, drying with absolute sodium sulfate, spin drying a solvent under reduced pressure, and then separating via column chromatography to obtain purified N-substituted aromatic formamide.
[0032] Example 1
[0033] In an air atmosphere, 0.2 mmol of aniline was magnetically stirred with 0.3 mmol of 2,2,2-trifluoroaryl ethanone and 0.4 mmol of potassium carbonate for 4 h at 60°C in DMSO, and monitoring was performed via TLC during the reaction until the completion of the reaction. Posttreatment was then performed and a proper amount of ethyl acetate was added for extraction, and the extract was dried with absolute sodium sulfate. The solvent was spin dried, and then purified N-phenyl benzamide was obtained by column chromatography separation. The separation yield: 93%.
[0034] 'H NMR (400 MHz, CDCL) 8 7.99 (s, 1H), 7.86 (s, 2H), 7.65 (s, 2H), 7.50 (d, J= 26.2 Hz, 3H), 7.36 (s, 2H), 7.15 (s, 1H). 13C NMR (101 MHz, CDCh) 8 165.85, 137.94, 134.98, 131.80, 129.06, 128.74, 127.04, 124.56, 120.29.
[0035] Example 2
[0036] In an air atmosphere, 0.2 mmol of p-toluidine was magnetically stirred with 0.3 mmol of 2,2,2-trifluoroaryl ethanone and 0.4 mmol of potassium carbonate for 4 h at 60°C in DMSO, and monitoring was performed via TLC during the reaction until the completion of the reaction. Posttreatment was then performed and a proper amount of ethyl acetate was added for extraction, and the extract was dried with absolute sodium sulfate. The solvent was spin dried and then purified N-(4-methylphenyl)benzamide was obtained by column chromatography separation. The separation yield: 86%.
[0037] 'H NMR (400 MHz, CDCh) 6 7.87 (t, J= 15.9 Hz, 3H), 7.48 (dd, J= 23.6, 7.6 Hz, 5H), 7.18 (t, J= 22.5 Hz, 2H), 2.33 (s, 3H).13C NMR (101 MHz, CDCh) 6 165.75, 135.39, 135.08, 134.22, 131.70, 129.56, 128.72, 127.03, 120.38, 20.91.
[0038] Example 2 mainly investigated applicability of an electron donating group (methyl)-containing aniline substrate. The results of this example showed that the electron donating substrate was similarly applicable to this reaction to obtain amide lb.
[0039] Example 3 a xr 1c
[0040] In an air atmosphere, 0.2 mmol of p-methoxyaniline was magnetically stirred with 0.3 mmol of 2,2,2-trifluoroaryl ethanone and 0.4 mmol of potassium carbonate for 4 h at 60°C in DMSO, and monitoring was performed via TLC during the reaction until the completion of the reaction. Posttreatment was then performed and a proper amount of ethyl acetate was added for extraction, and the extract was dried with absolute sodium sulfate. The solvent was spin dried and then purified N-(4-methoxyphenyl) benzamide was obtained by column chromatography separation. The separation yield: 80%.
[0041] 'H NMR (400 MHz, DMSO) 5 10.17 (s, 1H), 7.96 (d, J= 7.0 Hz, 2H), 7.70 (d, J = 9.0 Hz, 2H), 7.60 - 7.49 (m, 3H), 6.93 (d, J= 9.0 Hz, 2H), 3.74 (s, 3H).13C NMR (101 MHz, DMSO) 5 165.17, 155.59, 135.09, 132.28, 131.43, 128.39, 127.60, 122.04, 113.76, 55.20.
[0042] Example 3 mainly investigated applicability of an electron donating group (methoxy)-containing aniline substrate. The results of this example showed that the electron donating substrate was similarly applicable to this reaction to obtain amide 1c.
[0043] Example 4 ° rr I H Id
[0044] In an air atmosphere, 0.2 mmol of p-nitroaniline was magnetically stirred with 0.3 mmol of 2,2,2-trifluoroaryl ethanone and 0.4 mmol of potassium carbonate for 4 h at 60°C in DMSO, and monitoring was performed via TLC during the reaction until the completion of the reaction. Posttreatment was then performed and a proper amount of ethyl acetate was added for extraction, and the extract was dried with absolute sodium sulfate. The solvent was spin dried and then purified N-(4-nitrophenyl) benzamide was obtained by column chromatography separation. The separation yield: 60%.
[0045] 'H NMR (400 MHz, DMSO) 5 10.81 (s, 1H), 8.28 (d, J= 9.3 Hz, 2H), 8.07 (d, J = 9.3 Hz, 2H), 7.99 (d, J= 7.1 Hz, 2H), 7.65 (t, J= 7.3 Hz, 1H), 7.57 (t, J = 7.4 Hz, 2H).13C NMR (101 MHz, DMSO) 8 166.78, 145.97, 142.95, 134.70, 132.66, 129.00, 128.39, 125.27, 120.32.
[0046] Example 4 mainly investigated applicability of an electron withdrawing group(nitro)-containing aniline substrate. The results of this example showed that the electron withdrawing substrate was similarly applicable to this reaction to obtain amide Id.
[0047] Example 5
[0048] In an air atmosphere, 0.2 mmol of aniline was magnetically stirred with 0.3 mmol of 4-(trifluoroacetyl) toluene and 0.4 mmol of potassium carbonate for 4 h at 60°C in DMSO, and monitoring was performed via TLC during the reaction until the completion of the reaction. Posttreatment was then performed and a proper amount of ethyl acetate was added for extraction, and the extract was dried with absolute sodium sulfate. The solvent was spin dried and then purified 4-methyl-N-phenyl benzamide was obtained by column chromatography separation. The separation yield: 79%.
[0049] XH NMR (400 MHz, CDCh) 8 7.80 ( s,lH ), 7.77 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 7.6 Hz, 2H), 7.38 (d, J = 7.5 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 7.15 (s, 1H), 2.43 (s, 3H). 13C NMR (101 MHz, CDCh) 8 165.6, 142.4, 138.0, 132.1, 129.4, 129.1, 127.0, 124.4, 120.1, 21.5.
[0050] Example 5 mainly investigated applicability of an electron donating group (methyl)-containing trifluoroacetophenone substrate. The results of this example showed that the electron donating substrate was similarly applicable to this reaction to obtain amide le.
[0051] Example 6 O
[0052] In an air atmosphere, 0.2 mmol of ethylamine was magnetically stirred with 0.3 mmol of 2,2,2-trifluoroacetophenone and 0.4 mmol of potassium carbonate for 4 h at 60°C in DMSO, and monitoring was performed via TLC during the reaction until the completion of the reaction. Posttreatment was then performed and a proper amount of ethyl acetate was added for extraction, and the extract was dried with absolute sodium sulfate. The solvent was spin dried and then purified N-ethyl benzamide was obtained by column chromatography separation. The separation yield: 97%.
[0053] 'H NMR (400 MHz, CDC13) 6 7.76 (d, J = 7.8 Hz, 2H), 7.47 (t, J = 6.9 Hz, 1H), 7.39 (t, J = 7.5 Hz, 2H), 6.37 (s, 1H), 3.52 - 3.42 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H).13C NMR (101 MHz, CDCI3) 6 167.55, 134.79, 131.31, 128.52, 126.88, 34.95, 14.90.
[0054] Example 6 mainly investigated applicability of an alkylamine substrate. The results of this example showed that the electron donating substrate was similarly applicable to this reaction to obtain amine If.
[0055] For those skilled in the art, obviously, the present disclosure is not limited to the details of the above exemplary embodiments, and can be achieved in other specific forms without departing from the spirit or basic features of the present disclosure. Therefore, from any perspective, the embodiments should be regarded as being exemplary and non-limiting. The scope of the present disclosure is limited by the accompanying claims rather than the above description. Therefore, it is intended to include all changes within the meaning and scope of the equivalent elements of the claims within the present disclosure. Any reference numbers in claims should not be considered as limiting the involved claims.
[0056] In addition, it should be understood that although this specification is described according to the implementation methods, not every embodiment only includes an independent technical solution. This description of the specification is only for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.
Claims
WHAT IS CLAIMED IS:
1. A synthesis method of N-substituted aromatic formamide based on 2,2,2-trifluoroaryl ethanone, wherein N-substituted aromatic formamide is prepared in a reaction solvent in the presence of an alkali by using amine and a 2,2,2-trifluoroaryl ethanone reagent as raw materials, and the reaction process is as follows:Ar CF3K2CO3I2DMSO, 60°CAr NHwherein, Ar is substituted phenyl, and R is alkyl or substituted phenyl;the synthesis method specifically comprises the following operation steps:in an air atmosphere, magnetically mixing 0.1-0.5 mmol of amine with 0.2-1 mmol of 2,2,2-trifluoroaryl ethanone and 0.1-1 mmol of potassium carbonate for 2-4 h at 40-60°C in dimethyl sulfoxide (DMSO), monitoring via thin-layer chromatography (TLC) during the reaction until the completion of the reaction, posttreating, adding a proper amount of ethyl acetate for extraction, drying with absolute sodium sulfate, spin drying a solvent under reduced pressure, and then separating via column chromatography to obtain purified N-substituted aromatic formamide.
2. The synthesis method of N-substituted aromatic formamide based on 2,2,2-trifluoroaryl ethanone according to claim 1, the synthesis method specifically comprises the following operation steps: in an air atmosphere, magnetically mixing 0.2 mmol of amine with 0.3 mmol of 2,2,2-trifluoroaryl ethanone and 0.4 mmol of potassium carbonate for 4 h at 60°C in DMSO, monitoring via TLC during the reaction until the completion of the reaction, posttreating, adding a proper amount of ethyl acetate for extraction, drying with absolute sodium sulfate, spin drying a solvent under reduced pressure, and then separating via column chromatography to obtain purified N-substituted aromatic formamide.
3. The synthesis method of N-substituted aromatic formamide based on 2,2,2-trifluoroaryl ethanone according to claim 1, wherein the amine comprises any one of aniline, p-toluidine and ethylamine.
4. The synthesis method of N-substituted aromatic formamide based on 2,2,2-trifluoroaryl ethanone according to claim 1, wherein the 2,2,2-trifluoroaryl ethanone reagent comprises anyone of 2,2,2-trifluoroaryl ethanone and 4-(trifluoroacetyl)toluene.
5. The synthesis method of N-substituted aromatic formamide based on 2,2,2-trifluoroaryl ethanone according to claim 1, wherein the reaction solvent is DMSO.
6. The synthesis method of N-substituted aromatic formamide based on 2,2,2-trifluoroaryl ethanone according to claim 1, wherein the alkali is potassium carbonate.
7. The synthesis method of N-substituted aromatic formamide based on 2,2,2-trifluoroaryl ethanone according to claim 1, wherein the synthesis method comprises the following steps:in an air atmosphere, magnetically mixing 0.2 mmol of aniline with 0.3 mmol of 2,2,2-trifluoroaryl ethanone and 0.4 mmol of potassium carbonate for 4 h at 60°C in DMSO, monitoring via TLC during the reaction until the completion of the reaction, posttreating, adding a proper amount of ethyl acetate for extraction, drying with absolute sodium sulfate, spin drying a solvent under reduced pressure, and then separating via column chromatography to obtain purified N-substituted aromatic formamide.