Letter pubs.acs.org/journal/ascecg
Catalyst-Free Decarboxylative Trifluoromethylation/ Perfluoroalkylation of Benzoic Acid Derivatives in Water− Acetonitrile Dangui Wang, Jingxian Fang, Guo-Jun Deng, and Hang Gong* The Key Laboratory of Environmentally Friendly Chemistry and Application of the Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan 411105, People’s Republic of China S Supporting Information *
ABSTRACT: This study presents a mild and practical method for the catalyst-free decarboxylative trifluoromethylation/perfluoroalkylation of benzoic acid derivatives by using inexpensive NaSO2CF3 as a CF3-source and solid Na2S2O8 as an initiator. The environment-friendly transformation is performed at 30 °C in water−acetonitrile, and it can be easily scaled up to the gram level with a good yield. KEYWORDS: Trifluoromethylation, Metal-free, Decarboxylation, Environmentally friendly chemistry
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(Langlois’ reagent, 3.0 equiv)38 as CF3-source, and water/ acetonitrile (1.0 mL, 1:1) as the solvent at 30 °C under argon atmosphere (Table 1). The yield of the desired product was 67% (2a:3a = 46:21) (entry 1). First, the influence of reaction temperature was investigated, and results show that high temperature is unfavorable for this transformation (Table 1, entries 1−3). In studying the amount of CF3SO2Na, a slightly reduced yield of 57% can be obtained with better selectivity of mono substitution when 4 equiv of CF3SO2Na was used. Hence, the amount of 4 equiv of CF3SO2Na was used in the following study (Table 1, entries 1, 4−6). The reaction time was then studied, and the transformation was completed within 72 h; a prolonged reaction time is not beneficial for the reaction (Table 1, entries 5, 7−8). Several initiators were screened, and no better results were achieved (Table 1, entries 5, 9−11). A good yield of 77% was achieved when the amount of sodium persulfate was increased to 3 equiv (Table 1, entry 12). No better yield was observed when the amount of H3PO4 was adjusted (Table S1, entries 12, 15−18). Other additives such as HBF4, (n‑C4H9)4NBr, and N,N-diisopropylethylamine were also evaluated, but only poor yields were achieved (Table S1, entries 19−21). Water and other mixture solvents were also examined, but the yield was only poor to moderate (Table S1, entries 22− 29). When the reaction was conducted under air atmosphere, a slightly reduced yield of 62% was still obtained (Table 1, entry 15). By contrast, only a poor yield of 23% was achieved when the reaction was conducted under an atmosphere of oxygen (Table 1, entry 16). The scope of the substrate was examined using the reliable decarboxylative trifluoromethylation protocol (Tables 2 and S2). Nearly all benzoic acids substituted with electron-rich
INTRODUCTION Although trifluoromethyl is not a naturally occurring substance, it is still a popular component for numerous compounds.1−4 These compounds are widely applied in various fields, especially in pesticides and pharmaceuticals (Figure 1).5−9 The physical and biological properties, such as solubility, lipophilicity, and catabolic stability, of the parent molecules are remarkably modified by the trifluoromethyl group.5,10−12 Thus, developing methods for the selective introduction of trifluoromethyl group into organic molecules is of great interest for scientists. Many functionalized compounds, such as alkyl/ aryl halides or triflates, alkyl/aryl boronic derivatives, alkene, and alkyne were used as substrates for trifluoromethylation reactions.13 The direct C−H bond trifluoromethylation was also recently developed13−31 and reported by our group.32 In our previous work, arene was trifluoromethylated by using the inexpensive NaSO2CF3 (Langlois’ reagent) as the CF3-source and sodium persulfate as the initiator. When 2,4,6-trimethoxybenzoic acid was used as substrate, no desired direct C−H bond trifluoromethylation product was detected; however, a 67% yield of the decarboxylative trifluoromethylation product was obtained. Despite the development of the decarboxylative trifluoromethylation reaction for other types of substrates (Scheme 1, A−C),33−37 to the best of our knowledge, no decarboxylative trifluoromethylation reaction of aromatic carboxylic acid was reported. In the current study, a mild, persulfate-induced method for the metal-free decarboxylative trifluoromethylation reaction of aromatic carboxylic acid in the presence of water is described (Scheme 1E).
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RESULTS AND DISCUSSION The initial investigation commenced with the decarboxylative trifluoromethylation reaction of 2,4,6-trimethoxybenzoic acid using sodium persulfate (1.5 equiv) as the initiator, CF3SO2Na © 2017 American Chemical Society
Received: May 30, 2017 Revised: June 27, 2017 Published: July 14, 2017 6398
DOI: 10.1021/acssuschemeng.7b01705 ACS Sustainable Chem. Eng. 2017, 5, 6398−6403
Letter
ACS Sustainable Chemistry & Engineering
Figure 1. Examples of biologically active compounds of (trifluoromethyl)arenes.
groups were converted into the desired trifluoromethylation product at good yields (Table 2, 2a−j). The yields of 2c and 2d are lower than those of 2a and 2b due to the influence of steric hindrance of substituents. Particularly, the selectivity of this reaction is extraordinary when asymmetrical benzoic acid was used as substrate. For example, the substituted products in situ are the main product when 1e was used as the substrate, whereas they become the minor product when 1f was used as the substrate. Almost a similar regularity was observed in the cases of using 1g/1h and 1i/1j as the substrates. The decarboxylative perfluoroalkylation of benzoic acid derivatives was also conducted, and a good yield was still achieved (Table 2, 2k−o). Unfortunately, no desired product was produced when less electron-rich or electron-poor aromatic acids were used as substrates (Table S2, 2k−o). This transformation is highly dependent on the electronic degree of the substrate. This reaction can be easily scaled up to the half-gram level by using 1a (0.5 g, 2.36 mmol) as the substrate, Na2S2O8 (3.0
Scheme 1. Reported Decarboxylative Trifluoromethylation Reaction and Our Work
Table 1. Selected Optimization Resultsa
Entry
Initiator (equiv)
T (°C)
Yield (%) (2a:3a)
1b 2b 3b 4c 5 6d 7e 8f 9 10 11 12 13 14 15g 16h
Na2S2O8 (1.5) Na2S2O8 (1.5) Na2S2O8 (1.5) Na2S2O8 (1.5) Na2S2O8 (1.5) Na2S2O8 (1.5) Na2S2O8 (1.5) Na2S2O8 (1.5) K2S2O8 (1.5) (NH4)2S2O8 (1.5) t-BuOOH (1.5) Na2S2O8 (3) Na2S2O8 (2) Na2S2O8 (1) Na2S2O8 (3) Na2S2O8 (3)
30 50 80 30 30 30 30 30 30 30 30 30 30 30 30 30
67(46/21) 59(38/21) 20(8/12) 42(32/10) 57(49/8) 55(44/11) 52(42/10) 62(52/10) 23(15/8) 32(21/11) 10(8/2) 77(63/14) 67(51/16) 45(39/6) 62(56/6) 23
a
Unless otherwise noted, all reactions were conducted on a 0.1 mmol scale with 4 equiv of CF3SO2Na, initiator and H3PO4 (1.5 mol %) in a sealed tube in CH3CN:H2O (0.5 mL: 0.5 mL) under an atmosphere of argon for 72 h. Yields are detected by GC−MS using naphthalene as internal standard. b3 equiv. CF3SO2Na is used. c5 equiv. CF3SO2Na is used. d1.5 equiv. CF3SO2Na is used. eReaction time is 48 h. fReaction time is 96 h. g Under air atmosphere. hUnder O2 atmosphere. 6399
DOI: 10.1021/acssuschemeng.7b01705 ACS Sustainable Chem. Eng. 2017, 5, 6398−6403
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ACS Sustainable Chemistry & Engineering Table 2. Decarboxylative Trifluoromethylation/Perfluoroalkylation of Benzoic Acid Derivativesa
a
Unless otherwise noted, all reactions were conducted on a 0.1 mmol scale with RfSO2Na (4 equiv), Na2S2O8 (3 equiv), and H3PO4 (1.5 mol %) in a sealed tube in CH3CN:H2O (0.5 mL: 0.5 mL) under an atmosphere of argon for 72 h. The green star marks position is the original location of carboxyl. The isolated yields are presented. bCH3CN:H2O = 1 mL: 1 mL.
Scheme 2. Half-Gram Reaction
experiments indicated that this reaction probably occurs in two steps. The first step is decarboxylation, followed by trifluoromethylation. Radical inhibition experiments were then performed (Scheme 3, eqs 3−4). When 1 equiv of benzoquinone or 1,1-diphenylethylene was added, only poor or trace amount of the desired product was detected, respectively. Thus, this radical process can be efficiently blocked by these two radical inhibitors. A deuteration study was also conducted. We performed the decarboxylative trifluoromethylation reaction in the mixture solvents of CH3CN:D2O = 0.5 mL:0.5 mL (Scheme 3, eq 5). The result showed the high deuterium ratio of the desired product. Afterward, 2,4,6-trimethoxybenzoic acid, 1,3,5-trimethoxybenzene and 1,3,5-trimethoxy-2-(trifluoromethyl)benzene were treated with D2O in the absence of CF3SO2Na (Scheme 3, eqs 6−8). Both eq 6 and eq 7, the deuterated 1,3,5trimethoxybenzene were obtained as the mainly product. However, in the case of eq 8, only a poor deuterium ratio
equiv), CF3SO2Na (4.0 equiv), and H3PO4 (1.5 mol %) in a water−acetonitrile mixture (11.8 mL:11.8 mL) (Scheme 2). The mixture was stirred in a sealed tube under argon atmosphere at 30 °C for 5 days. A good yield of 68% can be obtained, which is comparable with the template reaction (Table 2, 2a). Several control experiments were conducted to explore the reaction mechanism (Scheme 3). First, the reaction was conducted using 2,4,6-trimethoxybenzoic acid (1a) as a substrate in the absence of CF3SO2Na, and the decarboxylation product was detected in an essentially quantitative yield (Scheme 3, eq 1). On the basis of our previous study, the decarboxylation product can be easily converted to 1,3,5trimethoxy-2-(trifluoromethyl)benzene (2a) at the standard reaction conditions.32 Afterward, when 2,4,6-trimethoxy-3(trifluoromethyl)benzoic acid was used in the absence of CF3SO2Na at the standard conditions, almost no decarboxylation product can be detected (Scheme 3, eq 2). These two 6400
DOI: 10.1021/acssuschemeng.7b01705 ACS Sustainable Chem. Eng. 2017, 5, 6398−6403
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ACS Sustainable Chemistry & Engineering Scheme 3. Control Experiments
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could be found. These results indicated that the reaction probably occurs in two steps, which containing decarboxylation-aromatization and followed by a trifluoromethylation process. On the basis of these results and our previous investigation,32 a reasonable mechanism was proposed (Scheme 4). The carboxyl radical was formed in the presence of Na2S2O8, followed by decarboxylation to access the phenyl radical. Then, a hydrogen of water is captured by the phenyl radical to achieve the arene (Cycle I). Afterward, the Cycle II, which had been described in our previous work,32 occurred which included a radical initial, followed by a radical addition, and the loss of hydrogen atom aromatization to form the target molecular (T.M.).
CONCLUSIONS
The present study described a practical method for the catalystfree decarboxylative trifluoromethylation of benzoic acid under mild reaction conditions using readily available CF3SO2Na as CF3-source. This strategy exhibits the advantages of water compatibility, operation safety, can be conducted at room temperature, and environment friendliness. In addition, this transformation can be easily scaled up to the gram level with good yield. Thus, the proposed strategy provides an avenue for introducing the trifluoromethyl and perfluoroalkyl groups into arenes. 6401
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Scheme 4. Proposed Mechanism for the Decarboxylative Trifluoromethylation of Benzoic Acid
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EXPERIMENTAL SECTION
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ASSOCIATED CONTENT
A solution of benzoic acid derivative (0.1 mmol), Na2S2O8 (3.0 equiv), CF3SO2Na (4.0 equiv), and H3PO4 (1.5 mol %) in a water− acetonitrile mixture (0.5 mL:0.5 mL) was stirred in a sealed tube under argon atmosphere at 30 °C for 72 h. The reaction mixture was then extracted with ethyl acetate. Afterward, the combined organic phase was dried with Na2SO4, and the solvent was evaporated in vacuo. The residue was purified by preparative thin-layer chromatography on silica gel with petroleum ether and ethyl acetate to yield the pure product. S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acssuschemeng.7b01705. General information, selected optimization results and some failed substrates, preparation of substrates, experimental procedure and characterization data for products, and copies of 1H, 19F and 13C NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*H. Gong. E-mail:
[email protected]. ORCID
Guo-Jun Deng: 0000-0003-2759-0314 Hang Gong: 0000-0003-4513-593X Author Contributions
The paper was written through contributions of all authors. All authors have given approval to the final version of the paper. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (No. 21402168), Scientific Research Foundation of Hunan Provincial Education Department (No. 15B232), and Hunan 2011 Collaborative Innovation Center of Chemical Engineering & Technology with Environmental Benignity and Effective Resource Utilization for their support of our research.
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REFERENCES
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