Study on the Synthesis and Biological Activity of Trifluoroacetamide Promoted by Base without Transition-Metal Participation

Abstract

We herein report a transition-metal-free coupling reaction that enables the efficient synthesis of trifluoroacetylaniline compounds using 1,1-dibromo-3,3,3-trifluoroacetone as the trifluoroacetylation reagent. The reaction conditions are mild and only one equivalent of base is required. The reaction exhibits good tolerance towards a variety of functional groups in the substrates. The biological bactericidal activities of two of the compounds were studied and it was found that one exhibits good bactericidal effects, with a bactericidal rate of over 99% against Bacillus subtilis. We believe that this research result will provide a good technical foundation for future drug-molecule screening.

Key words

trifluoroacetyl - aromatic amines - bactericidal activity - transition-metal free - dibromotrifluoroacetone

The synthesis of fluorinated organic molecules has become one of the most active and dynamic areas in chemistry.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] In fact, the fields of modern pharmaceuticals and plant protection agents as well as advanced materials, for example, energy technologies (batteries, etc.), would be impossible without appropriate organofluorine compounds. In this respect, the development of new synthetic methodologies for the preparation of fluorinated molecules is crucial. Although many elegant protocols for the introduction of fluorine atoms or fluoroalkyl groups directly into a given organic substrate have been disclosed in the past decades,[11–27] there remains a continuing interest in complementary and improved procedures, particularly in the development of new methods that can be applied on a practical scale.[28–34]

In the past few decades, many synthetic methods have been reported for the synthesis of trifluoroacetylaniline, for example, from N-formylaniline and trifluoromethane, which can be synthesized under the action of strong bases (Scheme [1a]).[35] Nitrobenzene substrates can also undergo reduction reactions with ethyl trifluoroacetate under hydrogenation conditions with supported nickel catalysts (Scheme [1b]).[36] Direct dehydration of aniline and trifluoroacetic acid under iron catalysis can be used to synthesize trifluoroacetylaniline (Scheme [1c]).[37] Heating 1,1,1-tribromo-3,3,3-trifluoropropanone with freshly distilled aniline also leads to the formation of trifluoroacetanilide (Scheme [1d]).[38] Indeed, there are many other reports of similar methods.[39] [40] [41] [42] [43] [44] However, there are still relatively few coupling reaction methods that do not use transition metals, especially in pharmaceutical chemistry where strict control of metal residues is required. This has driven researchers to develop new coupling reactions that do not require the participation of transition metals to achieve the synthesis of bioactive molecules. Based on this, we designed a coupling reaction between dibromotrifluoroacetone and aniline that proceeds under alkaline conditions to efficiently synthesize such compounds (Scheme [1e]).

Scheme 1 Synthesis strategy of trifluoroacetyl aniline

As shown in Table [1], O-hydroxyphenylamine (1a) was initially selected to react with 3,3-dibromo-1,1-trifluoroacetone (2) as a template. In the presence of sodium carbonate with 1,4-dioxane as the solvent, the reaction was carried out at 100 °C for 10 hours, and the target compound was generated with a yield of 39% (entry 1). We then screened the conditions of the reaction. First, we examined different types of bases and found that the reaction yield increased to 65% when sodium bicarbonate was used (entries 1–10). Next, we investigated the solvent used in the reaction. When 1,4-dioxane was used, the isolated yield of the reaction was optimal, reaching 65% (entries 10–17). Subsequently, we investigated the temperature required for the reaction (entries 18–21) and found that increasing or decreasing the temperature decreased the reaction yield. When the temperature was 120 °C, the yield was highest (78%; entry 20). Finally, we investigated the reaction time and found that after 12 hours reaction, the yield increased to 83% (entries 22–24). Thus, it was found that the optimal conditions for this reaction were 1a (1 mmol), 2 (2 mmol), sodium bicarbonate (2 mmol), 1,4-dioxane (2 mL), 120 °C, 12 h, which gave a reaction yield of 83% (entry 24).

Table 1 Optimization of Reaction Conditions^a

Entry	Base	Solvent	Temp (°C)	Time (h)	Yield (%)b
1	Na2CO3	1,4-dioxane	100	10	39
2	Et3N	1,4-dioxane	100	10	49
3	K2CO3	1,4-dioxane	100	10	20
4	KHCO3	1,4-dioxane	100	10	59
5	DMAP	1,4-dioxane	100	10	39
6	DBU	1,4-dioxane	100	10	20
7	DIPEA	1,4-dioxane	100	10	10
8	t-BuOK	1,4-dioxane	100	10	7
9	t-BuONa	1,4-dioxane	100	10	12
10	NaHCO3	1,4-dioxane	100	10	65
11	NaHCO3	MeCN	100	10	59
12	NaHCO3	hexane	100	10	0
13	NaHCO3	DMF	100	10	54
14	NaHCO3	MOE	100	10	7
15	NaHCO3	MePh	100	10	10
16	NaHCO3	THF	100	10	0
17	NaHCO3	IPA	100	10	<5
18	NaHCO3	1,4-dioxane	60	10	29
19	NaHCO3	1,4-dioxane	80	10	34
20	NaHCO3	1,4-dioxane	120	10	78
21	NaHCO3	1,4-dioxane	140	10	49
22	NaHCO3	1,4-dioxane	120	6	20
23	NaHCO3	1,4-dioxane	120	8	44
24	NaHCO3	1,4-dioxane	120	12	83

^a Reaction conditions: 1a (1.0 mmol), 2 (2.0 mmol), base (2.0 equiv), solvent (2.0 mL), 6–12 h, 60–140 °C. Note: IPA = isopropanol, MOE = 2-methoxyethanol, DMF = N,N-dimethylformamide.

^b Isolated yield.

In order to investigate the generality of this reaction, aniline derivatives with different substituents were studied. The results indicate that, irrespective of whether the substituents on aniline were electron-rich or electron-deficient, the corresponding target compounds were generated under the optimal reaction conditions (Table [2]). With electron-rich substituents on aniline, such as alkyl, methoxy, ethoxy, and hydroxyl groups, most of the corresponding target products 3a–j were obtained with high yields. When electron-deficient substituents were present on the aniline, such as fluorine, chlorine, bromine, iodine, and cyanide, the corresponding target products 3k–q were also obtained with good yields. At the same time, we also investigated compounds with multiple substituents on aniline, and the corresponding target products 3r–ab were obtained with moderate to high yields.

Table 2 Substrate Scope of Aniline^a

^a Reaction conditions: 1 (1.0 mmol), 2 (2.0 mmol), NaHCO₃ (2.0 mmol), 1,4-dioxane (2.0 mL), 120 °C, 12 h. Isolated yield.

Finally, we also conducted biological activity tests on the synthesized trifluoromethylaniline derivatives and found that compounds 3z and 3aa have different bactericidal effects on different bacterial strains (Table [3]), especially on Staphylococcus aureus, Salmonella enteritidis, Pseudomonas aeruginosa, and Bacillus subtilis. For Bacillus subtilis, compound 3z exhibited a sterilization rate of over 99% (entry 4). These biological activity experimental results provide a scientific basis for future drug screening.

Table 3 Biological Sterilization Studies

Entry	Strain	Bactericidal molecule	Sterilization conc. (CFU/mL)	Sterilization rate (%)
1	Staphylococcus aureus	3z	9 × 106	95.86
	Staphylococcus aureus	3aa	5 × 106	62.28
2	Salmonella enteritidis	3z	2 × 106	78.52
	Salmonella enteritidis	3aa	2 × 106	84.65
3	Pseudomonas aeruginosa	3z	1 × 106	30.33
	Pseudomonas aeruginosa	3aa	1 × 106	48.87
4	Bacillus subtilis	3z	1 × 104	99.89
	Bacillus subtilis	3aa	4 × 105	93.77

Scheme 2 Possible reaction mechanism.

To summarize, we have developed a transition-metal-free coupling reaction for the efficient synthesis of trifluoroacetylaniline compounds. This method features mild conditions and does not require transition-metal catalysts or ligands. Only a base is needed to achieve this chemical conversion process, and the substrate range is wide. More importantly, we conducted biological sterilization experiments and found that two compounds had very good bactericidal effects, especially against Bacillus subtilis. This provides a technical basis for future biological activity research.

Conflict of Interest

The authors declare no conflict of interest.

• References and Notes

• 1 Key BD, Howell RD, Criddle CS. Environ. Sci. Technol. 1997; 31: 2445
• 2 Champagne PA, Desroches J, Hamel J.-D, Vandamme M, Paquin J.-F. Chem. Rev. 2015; 115: 9073
• 3 Chen C.-P, Wang C, Zhang J.-Y, Zhao Y.-S. J. Org. Chem. 2014; 80: 942
• 4 Zhou Y, Wang J, Gu Z.-N, Wang S.-N, Zhu W, Aceña JL, Soloshonok VA, Izawa K, Liu H. Chem. Rev. 2016; 116: 422
• 5 Wang K, Kong W.-Q. ACS Catal. 2023; 13: 12238
• 6 Zhao Y.-Y, Gao L, Li H.-G, Sun P.-W, Meng F.-F, Zhang Y, Xie Y.-T, Sun B.-Q, Zhou S, Ma Y, Xiong L.-X, Yang N, Li Y.-X, Li Z.-M. J. Agric. Food Chem. 2020; 68: 11282
• 7 Campbell MG, Ritter T. Org. Process Res. Dev. 2014; 18: 474
• 8 Campbell MG, Ritter T. Chem. Rev. 2014; 115: 612
• 9 Yerien DE, Barata-Vallejo S, Postigo A. Chem. Eur. J. 2017; 23: 14676
• 10 He Z.-B, Hu M.-Y, Luo T, Li L.-C, Hu J.-B. Angew. Chem. Int. Ed. 2012; 51: 11545
• 11 Zhu J.-S, Liu Y.-F, Shen Q.-L. Angew. Chem. Int. Ed. 2016; 55: 9050
• 12 Xiao H.-W, Zhang Z.-Z, Fang Y.-W, Zhu L, Li C.-Z. Chem. Soc. Rev. 2021; 50: 6308
• 13 Li G.-B, Zhang C, Song C, Ma Y.-D. Beilstein J. Org. Chem. 2018; 14: 155
• 14 Gietter-Burch AA. S, Devannah V, Watson DA. Org. Lett. 2017; 19: 2957
• 15 Morstein J, Hou H.-Y, Cheng C, Hartwig JF. Angew. Chem. Int. Ed. 2016; 55: 8054
• 16 Singh RP, Ghoshal T, Mishra V. Asian J. Org. Chem. 2024; 13: e202400179
• 17 Amii H. Chem. Rec. 2023; 23: e202300154
• 18 Wang H.-Z, Sun X, Linghu C.-C, Deng Y, Wang Y.-P, Wei C.-Y, Wang J, Zhang L. Tetrahedron Lett. 2023; 118: 154385
• 19 Liu J, Xiao Y.-S, Hao J, Shen Q.-L. Org. Lett. 2023; 25: 1204
• 20 Zhang B, Peng Q.-P, Guo D.-H, Wang J. Org. Lett. 2020; 22: 443
• 21 Jiang C, Wang L, Zhang H.-G, Chen P.-H, Guo Y.-L, Liu G.-S. Chem 2020; 6: 2407
• 22 Zhou Y.-R, Zhang C.-Y, Yuan J.-J, Yang Q, Xiao Q, Peng Y.-Y. Tetrahedron Lett. 2016; 57: 3222
• 23 Li B.-W, Zeng W.-B, Wang L, Geng Z.-S, Loh T.-P, Xie P.-Z. Org. Lett. 2021; 23: 5235
• 24 Zhang W, Lin J.-H, Wu W.-F, Cao Y.-C, Xiao J.-C. Chin. J. Chem. 2019; 38: 169
• 25 Yang X, Sun R, Li S, Zheng X.-L, Yuan M.-L, Xu B, Jiang W.-D, Chen H.-Y, Fu H, Li R.-X. Org. Lett. 2020; 22: 7108
• 26 Alam MM, Varala R, Seema V. Mini-Rev. Org. Chem. 2024; 21: 455
• 27 Rossen K. Org. Process Res. Dev. 2023; 27: 1421
• 28 Xue J.-H, Li Y, Liu Y, Li Q.-J, Wang H.-G. Angew. Chem. Int. Ed. 2024; 63: e202319030
• 29 Hong J.-Q, Wang G.-F, Huo L.-G, Zheng C.-G. Chin. J. Chem. 2017; 35: 1761
• 30 Liu P, Lei Z.-L, Peng Y.-Y, Liu Z.-J, Zhu F.-Q, Liu J.-T, Wu F.-H. Adv. Synth. Catal. 2018; 360: 3418
• 31 Kumar A, Mathew S, Jamali MF, Ahamad S, Kant R, Mohanan K. Adv. Synth. Catal. 2023; 365: 2218
• 32 Wang L.-B, Wang J.-P, Ye S.-T, Jiang B.-H, Guo Z.-H, Mumtaz Y, Yi W.-B. Angew. Chem. Int. Ed. 2022; 61: e202212115
• 33 Nguyen TT. ChemistrySelect 2020; 5: 12148
• 34 Xu J, Cheng K, Shen C, Bai R, Xie Y, Zhang P. ChemCatChem 2018; 10: 965
• 35 Hyune-Jea L, Jeong-Un J, Se-Jun Y, Dong-Pyo K, Heejin K. Nat. Commun. 2023; 14: 1231
• 36 Gao J, Ma R, Poovan F, Zhang L, Atia H, Kalevaru NV, Sun W, Wohlrab S, Chusov DA, Wang N, Jagadeesh R, Beller M. Nat. Commun. 2023; 14: 5013
• 37 Obieta M, Urgoitia G, Herrero MT, SanMartin R. Catal. Sci. Technol. 2024; 14: 478
• 38 Mcbee ET, Burton TM. J. Am. Chem. Soc. 1952; 74: 3902
• 39 Li S.-Y, Yang X.-Y, Shen P.-H, Xu L, Xu J, Zhang Q, Xu H.-J. J. Org. Chem. 2023; 88: 17284
• 40 Lu B, Zhang Z.-H, Jiang M, Liang D, He Z.-W, Bao F.-S, Xiao W.-J, Chen J.-R. Angew. Chem. Int. Ed. 2023; 62: e202309460
• 41 Zhao T.-F, Xu X.-L, Sun W.-Y, Lu Y. Org. Lett. 2023; 25: 4968
• 42 Huang Y, Wan Y.-C, Shao Y, Zhan L.-W, Li B.-D, Hou J. Green Chem. 2023; 25: 8280
• 43 Großmann LM, Beier V, Duttenhofer L, Lennartz L, Opatz T. Chem. Eur. J. 2022; 28: e202201768
• 44 Liu C, Li K, Shang R. ACS Catal. 2022; 12: 4103

Publication History

Received: 04 February 2025

Accepted after revision: 31 March 2025

Accepted Manuscript online:
01 April 2025

Article published online:
17 June 2025