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Article

Design, Catalyst-Free Synthesis of New Novel α-Trifluoromethylated Tertiary Alcohols Bearing Coumarins as Potential Antifungal Agents

by
Shengfei Jiang
1,
Guoyu Yang
1,
Lijun Shi
1,
Liangxin Fan
1,
Zhenliang Pan
1,
Caixia Wang
1,
Xiaodan Chang
1,
Bingyi Zhou
1,
Meng Xu
2,
Lulu Wu
1,* and
Cuilian Xu
1,*
1
College of Sciences, Henan Agricultural University, Zhengzhou 450002, China
2
Department of Information, The First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(1), 260; https://doi.org/10.3390/molecules28010260
Submission received: 1 December 2022 / Revised: 23 December 2022 / Accepted: 26 December 2022 / Published: 28 December 2022
(This article belongs to the Special Issue Advances of Heterocyclic Chemistry with Antibacterial and Antifungal Activity)
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Abstract

:
A new method for the synthesis of α-trifluoromethylated tertiary alcohols bearing coumarins is described. The reaction of 3-(trifluoroacetyl)coumarin and pyrrole provided the target compounds with high yields under catalyst-free, mild conditions. The crystal structure of compound 3fa was investigated by X-ray diffraction analysis. The biological activities, such as in vitro antifungal activity of the α-trifluoromethylated tertiary alcohols against Fusarium graminearum, Fusarium oxysporum, Fusarium moniliforme, Rhizoctonia solani Kuhn, and Phytophthora parasitica var nicotianae, were investigated. The bioassay results indicated that compounds 3ad, 3gd, and 3hd showed broad-spectrum antifungal activity in vitro. Compound 3cd exhibited excellent fungicidal activity against Rhizoctonia solani Kuhn, with an EC50 value of 10.9 μg/mL, which was comparable to that of commercial fungicidal triadimefon (EC50 = 6.1 μg/mL). Furthermore, molecular docking study suggested that 3cd had high binding affinities with 1W9U, like argifin.

1. Introduction

Trifluoromethylated compounds, due to their unique properties, are of utmost interest for a wide cross-section of chemists [1,2,3,4,5]. Among them, α-trifluoromethylated tertiary alcohol motifs are found in various pharmaceuticals (Figure 1) [6,7,8,9,10,11,12,13]. For example, α-trifluoromethylated tertiary alcohol A and efavirenz are HIV reverse transcriptase inhibitors, B1653048 and MK-0633, respectively, are glucorticoid agonist and 5-lipoxygenase inhibitor.
Therefore, several examples of the synthesis of trifluoromethylated tertiary alcohols have been described [14,15,16,17,18]. From all the methodologies described, the Friedel−Crafts alkylation reaction with trifluoromethyl ketones is one of the most straightforward approaches for the synthesis of this kind of tertiary alcohols [19,20,21,22]. Among these reported examples, most of them use trifluoromethyl ketones as acceptors in addition reactions (Figure 2a) [23,24,25]. Interestingly, we noted that when α,β-unsaturated trifluoromethyl ketones were used as acceptors, the adducts are 1,4-addition rather than 1,2-addition (Figure 2b) [26,27,28,29]. As a part of our continuing work in the functionalization of coumarins [30,31,32,33,34], coumarin-bearing α,β-unsaturated trifluoromethyl ketones were selected as electrophiles instead of trifluoromethyl ketones to obtain trifluoromethylated tertiary alcohols (Figure 2c).
Coumarin is an important heterocyclic skeleton frequently found in numerous natural products, pharmaceutical molecules, fluorescent probes, and materials [35,36,37,38,39,40,41,42]. The combination of some privileged structures, a benzopyrone ring, a trifluoromethyl moiety, and a pyrrole ring for the synthesis of quaternary carbon organic molecules could be of significant importance, especially for new drugs and materials.
In this paper, we describe the first synthetic method for the preparation of α-trifluoromethylated tertiary alcohols bearing coumarins. Our approach is based on the two-component reaction of 3-(trifluoroacetyl)coumarin and pyrrole, and this method required neither catalyst/additive nor special conditions. In addition, the in vitro antifungal activity of the title compounds was also studied.

2. Results and Discussion

We readily prepared 3-(trifluoroacetyl)coumarin 1a in two steps and directly used it as an electrophile for the Friedel–Crafts alkylation of 2-methylpyrrole 2a. During the process of exploring reaction conditions, we were initially pleased to find that the reaction proceeded smoothly in CH2Cl2 at room temperature to provide the desired product 3aa with 46% yield in the presence of 5 mol % of AlCl3 (Table 1, entry 1). The success indicated that the reaction could be promoted by Lewis acid. Subsequently, a series of Lewis acids were screened, and the reactions could proceed (Table 1, entries 2–6). However, unfortunately, only low yields of tertiary alcohol product were formed. To our surprise, 97% yield was observed by performing the reaction in the absence of catalyst (Table 1, entry 7). Finally, the reaction media were screened. Solvent evaluation indicated that the solvents have a remarkable influence on the yields (Table 1, entries 7–15). The yield sharply decreased when chloroform, ethyl acetate, acetonitrile, toluene, and tetrahydrofuran were used as the solvents (Table 1, entries 8–12). Methylene chloride was the best solvent, giving the highest yield of 97%. Unfortunately, the yield sharply decreased when reducing the reaction temperature to 0 ℃ (Table 1, entry 16).
Having established the preferred reaction conditions, we next examined the substrate scope of the Friedel–Crafts reaction (Table 2). A range of 3-(trifluoroacetyl)coumarins with different substituents at the 6-, 7-, or 8- positions proceeded smoothly to afford the corresponding α-trifluoromethyl tertiary alcohols 3aa–ia with excellent yields. Subsequently, pyrroles 2b–f with different groups were also tested for this synthesis. They proceeded well, furnishing the desired products 3ab–af with moderate to excellent yields. The position and electronic property of substituents had a remarkable influence on the yields. The pyrrole ring with electron-donating substituents at the 2-, 3-, or 4- positions proceeded smoothly to afford the corresponding α-trifluoromethyl tertiary alcohols with excellent yields, while the presence of electron-donating substituents in the 2- and 5- positions had a detrimental effect on the yield, due to the activity of the 2-position pyrrole higher than the 3-positon. It was gratifying that excellent yields could be achieved by adding Sc(OTf)3 and increasing the reaction temperature. Unfortunately, the pyrrole ring with an electron-deficient group was an infeasible substrate, presumably because electron withdrawal affected the activity of the pyrrole. Notably, when the pyrrole and N-methylpyrrole were employed, a comparable yield was obtained.
To test the feasibility of potential large-scale application of the process, the reaction of 3-(trifluoroacetyl)coumarin 1a with 2-methylpyrrole 2a was carried out at the 10 mmol scale under the standard conditions (Scheme 1). The reaction furnished a 95% yield of the product 3aa, which is quite comparable to the yield obtained in the small scale reaction (97% yield).
To determine the structures of the products, a single crystal of compound 3fa was obtained (Figure 3). The structures of other products can therefore be determined by analogy.
The in vitro antifungal activity of target compounds 3aa-3hd against six representative phytopathogens is summarized in Table 3. Triadimefon was used as a positive control at a concentration of 10 μg/mL. In general, the title compounds exhibited a certain degree of fungicidal activity at a concentration of 500 μg/mL. Among them, compounds 3ad, 3bd, and 3cd showed over 90% inhibition against F. graminearum (from corn). Compounds 3ad, 3bd, 3gd, and 3hd showed over 80% inhibition against F. oxysporum. Compounds 3ad and 3bd showed over 80% inhibition against F. graminearum (from wheat). In particular, 3ad, 3gd, and 3hd exhibited excellent activity (>98%) against R. solani Kuhn. Compounds 3ac, 3ad, 3bd, 3gd, and 3hd exhibited higher antifungal activity (> 80%) against P. parasitica var nicotianae. Furthermore, it was also worth noting that 3ad, 3gd, and 3hd exhibited broad-spectrum antifungal activity and could be considered as new fungicidal leads for further optimization.
The in vitro fungicidal activity of the title compounds against six phytopathogens showed that the substituents have a great impact on the activity. Overall, the fungicidal activity of 3-ethyl-2,4-dimethyl-1H-pyrrole derivatives (3ad, 3bd, 3cd, 3gd, and 3hd) showed generally higher inhibition against the tested fungi than other substituted pyrrole derivatives.
Several compounds with higher preliminary antifungal activities at a concentration of 500 μg/mL were selected for determination of the median effective concentration (EC50) values. As shown in Table 4, four compounds displayed good fungicidal activity against R. solani Kuhn. Among them, compound 3cd was the most potent and had the EC50 values of 10.9 μg/mL. The results indicated that most of the coumarin derivatives containing α-trifluoromethylated tertiary alcohols exhibited good fungicidal activity.
Studies have reported that coumarin compounds can bind with the groove of chitinese and revealed better fungal inhibitory activity [43]. The molecular docking of the compound 3cd with 1W9U was conducted to explore the probable interaction with chitinese, and argifin was used as the standard of comparison. As can be seen from Figure 4, compared with argifin, the coumarin derivative 3cd shows some similar aminoacid residues interacting with the receptor. For instance, TYR 245 formed a strong hydrogen bond with the fluorine that emerged as a hydrogen bond donor in the title compound. Then, another hydrogen bond appeared between the hydrogen in the pyrrole ring and ASP 246. It is worth noting that the target compound bonds to GLU 177 by a strong hydrogen bond, while argifin bonds to GLU 177 by the Van der Waals force. Although 3cd does not bind to GLU 178 by hydrogen bond as argifin does, it also binds to GLU 178 by Pi-Pi stacked interaction. Concurrently, the title compound 3cd connected with the TRP52, PHE76, GLY136, TRP137, PHE251, and TRP384 residues, which also formed weak interactions with the chitinese inhibitor argifin. As can be seen from the above results, our synthesized coumarin compounds are expected to be novel chitinese inhibitors, and the relative work is on the way.

3. Materials and Methods

3.1. Chemicals and Instruments

All chemicals, except 3-(trifluoroacetyl)coumarin 1, which was synthesized according our reported procedure, were purchased from commercial sources and used without further purification. 1H NMR, 19F NMR, and 13C NMR spectra were obtained using a Bruker DPX-400 spectrometer (Brucker Technologies Co., Karlsruhe, Germany) in CDCl3 or DMSO solution with TMS as an internal standard. HR-MS(APCI) spectra were performed using a Waters Q-Tof MicroTM instrument (Thermo Fisher Scientific, Waltham, Massachusetts, USA), and X-rays were measured at 293 K on a Rigaku RAXIAS-IV type diffractometer (Brucker Technologies Co., Karlsruhe, Germany). Most reaction yields, except compound 3fa, were not optimized. CCDC 2,167,896 contains the supplementary crystallographic data for this paper (Table S1 in the Supplement Materials). These data may be obtained free of charge via http://www.ccdc.cam.ac.uk; access on 15 November 2022.

3.1.1. General Procedure for the Preparation of Compounds 3aa–3af

A mixture of 3-(trifluoroacetyl)coumarin (1.0 mmol) and pyrrole (1.0 mmol) was stirred in methylene chloride (10 mL) at room temperature. After completion of the reaction, the mixture was concentrated under vacuum to yield the crude product, which was further purified by column chromatography.
To a mixture of 3-(trifluoroacetyl)coumarin (1.0 mmol) and pyrrole (1.0 mmol) in methylene chloride (10 mL) was added Sc(OTf)3 (5%), and the resulting mixture was heated under reflux. After completion of the reaction, the mixture was concentrated under vacuum to yield the crude product, which was further purified by column chromatography.

3.1.2. Compounds Data

3-(2,2,2-Trifluoro-1-hydroxy-1-(5-methyl-1H-pyrrol-2-yl)ethyl)-2H-chromen-2-one (3aa): Light Brown solid, mp: 134.5-135.6 °C. 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.87 (s, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.40–7.32 (m, 2H), 7.28 (s, 1H), 6.25 (s, 1H), 5.92 (s, 1H), 2.26 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.47 (C=O), 153.22, 145.16, 133.21, 129.12, 128.97, 125.29, 124.49 (q, J = 286.6 Hz, C-CF3), 123.50, 122.35, 118.39, 116.60, 108.76, 106.82, δ 76.71 (q, J = 31.3 Hz, CF3), 12.96. 19F NMR (376 MHz, CDCl3) δ -78.01(CF3). HRMS (APCI): m/z calculated for C16H11F3NO3 [M-H]− 322.0691, found: 322.0685.
6-Methyl-3-(2,2,2-trifluoro-1-hydroxy-1-(5-methyl-1H-pyrrol-2-yl)ethyl)-2H-chromen-2-one (3ba): Light yellow solid, mp: 207.9–208.7 °C. 1H NMR (400 MHz, DMSO-d6) δ10.46 (s, 1H), 8.29 (s, 1H), 7.70 (s, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.16 (s, 1H), 6.01 (s, 1H), 5.69 (s, 1H), 2.38 (s, 3H), 2.12 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 158.48(C=O), 152.02, 143.74, 134.41, 133.92, 129.46, 128.37, 125.48, 125.30 (q, J = 287.4 Hz, C-CF3), 124.53, 118.64, 115.98, 107.68, 105.78, δ 74.36 (q, J = 29.9 Hz, CF3), 20.68, 13.09. 19F NMR (376 MHz, DMSO-d6) δ -74.08(CF3). HRMS (APCI): m/z calculated for C17H13F3NO3 [M-H]− 336.0848, found: 336.0833.
6-Chloro-3-(2,2,2-trifluoro-1-hydroxy-1-(5-methyl-1H-pyrrol-2-yl)ethyl)-2H-chromen-2-one (3ca): White solid, mp: 235.9-236.5 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.45 (s, 1H), 8.13 (d, J = 2.5 Hz, 1H), 7.71 (dd, J = 8.8, 2.6 Hz, 1H), 7.48 (d, J = 8.9 Hz, 1H), 7.20 (s, 1H), 6.01 (s, 1H), 5.69 (s, 1H), 2.11 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 157.47(C=O), 152.62, 142.80, 132.58, 129.50, 128.95, 128.81, 128.38, 126.01, 125.35, 125.20(q, J = 287.4 Hz, C-CF3), 120.41, 118.23, 107.69, 105.86, 74.07(q, J = 30.1 Hz, CF3), 13.09. 19F NMR (376 MHz, DMSO-d6) δ -73.76(CF3). HRMS (APCI): m/z calculated for C16H10ClF3NO3 [M-H]− 356.0301, found: 356.0295.
6-Bromo-3-(2,2,2-trifluoro-1-hydroxy-1-(5-methyl-1H-pyrrol-2-yl)ethyl)-2H-chromen-2-one (3da): Cyan solid, mp: 236.5–236.9 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.43 (s, 1H), 8.24 (d, J = 2.3 Hz, 1H), 7.81 (dd, J = 8.8, 2.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.17 (s, 1H), 6.01 (s, 1H), 5.68 (s, 1H), 2.11 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 157.41(C=O), 153.01, 142.70, 135.33, 131.94, 128.36, 125.94, 125.34, 125.20 (q, J = 287.3 Hz, C-CF3), 120.90, 118.50, 116.58, 107.67, 105.84, 74.07 (q, J = 30.3 Hz, CF3), 13.09. 19F NMR (376 MHz, DMSO-d6) δ -73.78(CF3). HRMS (APCI): m/z calculated for C16H10BrF3NO3 [M-H]− 399.9796, found: 399.9782.
7-Methoxy-3-(2,2,2-trifluoro-1-hydroxy-1-(5-methyl-1H-pyrrol-2-yl)ethyl)-2H-chromen-2-one (3ea): White solid, mp: 160.5-161.8 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.27 (s, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.09 (s, 1H), 7.04 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 8.6, 2.4 Hz, 1H), 6.01 (s, 1H), 5.68 (s, 1H), 3.88 (s, 3H), 2.12 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 163.53(C=O), 158.79, 155.83, 143.94, 130.98, 128.30, 125.65, 125.40 (q, J = 287.5 Hz, C-CF3), 120.75, 113.20, 112.48, 107.63, 105.73, 100.51, 74.31 (q, J = 60.1, 30.1 Hz, CF3), 56.52, 13.10. 19F NMR (376 MHz, DMSO-d6) δ -74.31(CF3). HRMS (APCI): m/z calculated for C17H13F3NO4 [M-H]− 352.0797, found: 352.0783.
8-Methoxy-3-(2,2,2-trifluoro-1-hydroxy-1-(5-methyl-1H-pyrrol-2-yl)ethyl)-2H-chromen-2-one (3fa): Pink solid, mp: 198.1-198.6 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.36 (s, 1H), 7.46 (dd, J = 7.1, 1.9 Hz, 1H), 7.40–7.29 (m, 2H), 7.15 (d, J = 0.9 Hz, 1H), 6.01 (s, 1H), 5.69 (s, 1H), 3.93 (s, 3H), 2.11 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.02(C=O), 147.06, 145.28, 142.86, 128.75, 125.17, 124.47 (q, J = 286.7 Hz, C-CF3), 123.46, 122.50, 120.22, 119.05, 114.72, 108.69, 106.77, 76.68 (q, J = 31.3 Hz, CF3), 56.35, 12.93. 19F NMR (376 MHz, CDCl3) δ -78.04(CF3). HRMS (APCI): m/z calculated for C17H13F3NO4 [M-H]− 352.0797, found: 352.0791.
6,8-Dichloro-3-(2,2,2-trifluoro-1-hydroxy-1-(5-methyl-1H-pyrrol-2-yl)ethyl)-2H-chromen-2-one (3ga): Light yellow solid, mp: 168.5-169.1 °C. 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.76 (s, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.43 (d, J = 2.3 Hz, 1H), 6.88 (s, 1H), 6.22 (s, 1H), 5.91 (s, 1H), 2.26 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 160.77(C=O), 147.55, 143.78, 132.98, 130.53, 129.39, 128.53, 126.86, 124.71, 124.24 (q, J = 286.7 Hz, C-CF3). 122.72, 122.63, 120.13, 119.98, 76.73 (q, J = 31.5 Hz, CF3), 12.92. 19F NMR (376 MHz, CDCl3) δ -77.71(CF3). HRMS (APCI): m/z calculated for C16H9Cl2F3NO3 [M-H]− 389.9912, found: 389.9903.
6,8-Dibromo-3-(2,2,2-trifluoro-1-hydroxy-1-(5-methyl-1H-pyrrol-2-yl)ethyl)-2H-chromen-2-one (3ha): Cyan solid, mp: 162.1–163.2 °C. 1H NMR (400 MHz, CDCl3) δ8.47 (s, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.74 (s, 1H), 7.61 (d, J = 2.2 Hz, 1H), 6.87 (s, 1H), 6.23 (s, 1H), 5.91 (s, 1H), 2.26 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 160.85(C=O), 149.06, 143.75, 138.01, 130.57, 129.38, 124.64, 124.25 (q, J = 287.0 Hz, C-CF3), 122.74, 120.53, 117.88, 111.52, 108.96, 106.95, 76.69 (q, J = 31.7 Hz, CF3), 12.95. 19F NMR (376 MHz, CDCl3) δ -77.71(CF3). HRMS (APCI): m/z calculated for C16H9Br2F3NO3 [M-H]− 479.8881, found: 479.8868.
3-(2,2,2-Trifluoro-1-hydroxy-1-(5-methyl-1H-pyrrol-2-yl)ethyl)-2H-benzo[h]chromen-2-one (3ia): Tawny solid, mp: 192.0-192.9 °C. 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.54 (s, 1H), 8.12–8.00 (m, 2H), 7.91 (d, J = 8.1 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.51–7.40 (m, 2H), 7.26 (s, 1H), 6.39 (s, 1H), 6.01 (s, 1H), 2.28 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.56(C=O), 153.31, 141.04, 134.78, 130.47, 129.16, 129.01, 128.97, 128.90, 126.70, 124.65 (q, J = 286.8 Hz, C-CF3), 123.60, 121.48, 121.04, 116.24, 112.91, 108.65, 107.03, 76.95 (q, J = 31.2 Hz, CF3), 12.97. 19F NMR (376 MHz, CDCl3) δ -78.07(CF3). HRMS (APCI): m/z calculated for C20H13F3NO3 [M-H]− 372.0848, found: 372.0838.
3-(1-(3,5-Dimethyl-1H-pyrrol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-2H-chromen-2-one (3ab): Pink solid, mp: 131.7–132.8 °C. 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.78 (s, 1H), 7.57–7.47 (m, 2H), 7.33–7.27 (m, 2H), 7.17 (s, 1H), 6.26 (s, 1H), 5.62 (d, J = 3.1 Hz, 1H), 2.14 (s, 3H), 1.78 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.74(C=O), 153.09, 142.52, 133.01, 129.11, 128.81, 127.39 (q, J = 286.7 Hz, C-CF3), 127.25, 125.31, 123.10, 118.92, 118.19, 118.01, 116.66, 110.71, 76.50 (q, J = 31.3 Hz, CF3), 12.91, 12.48. 19F NMR (376 MHz, CDCl3) δ -75.55(CF3). HRMS (APCI): m/z calculated for C17H13F3NO3 [M-H]− 336.0848, found: 336.0833.
3-(1-(3,5-Dimethyl-1H-pyrrol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-8-methoxy-2H-chromen-2-one (3fb): Orange solid, mp: 67.1-68.5 °C. 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.83 (s, 1H), 7.33–7.26 (m, 2H), 7.14 (dd, J = 7.1, 5.4 Hz, 2H), 6.40 (s, 1H), 5.69 (d, J = 3.1 Hz, 1H), 3.98 (s, 3H), 2.23 (s, 3H), 1.86 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.34(C=O), 147.08, 142.74, 127.28, 125.25, 124.58 (q, J = 286.4 Hz, C-CF3), 123.27, 120.33, 120.24, 118.91, 118.86, 118.05, 114.62, 110.69, 76.54 (q, J = 31.1 Hz, CF3), 56.31, 12.87, 12.50. 19F NMR (376 MHz, CDCl3) δ -75.57(CF3). HRMS (APCI): m/z calculated for C18H15F3NO3 [M-OH]+ 350.0999, found: 350.1008.
3-(1-(2,5-Dimethyl-1H-pyrrol-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)-2H-chromen-2-one (3ac): Cyan solid, mp: 109.7–110.8 °C. 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.73 (s, 1H), 7.59 (t, J = 8.5 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.40–7.28 (m, 2H), 6.59 (s, 1H), 5.90 (s, 1H), 2.21 (s, 3H), 2.16 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.19(C=O), 153.26, 144.34, 132.76, 128.94, 125.92, 125.34 (q, J = 287.4 Hz, C-CF3), 125.22, 125.10, 124.76, 121.07, 118.59, 116.54, 114.97, 106.45, 77.99 (q, J = 30.0 Hz, CF3), 12.96, 12.80. 19F NMR (376 MHz, CDCl3) δ -76.82(CF3). HRMS (APCI): m/z calculated for C17H13F3NO2 [M-OH]+ 320.0893, found: 320.0917.
3-(1-(2,5-Dimethyl-1H-pyrrol-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)-6-methyl-2H-chromen-2-one (3bc): White solid, mp: 161.2–162.0 °C. 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 7.67 (s, 1H), 7.39 (dd, J = 8.5, 1.3 Hz, 1H), 7.29 (d, J = 7.1 Hz, 1H), 6.61 (s, 1H), 5.89 (s, 1H), 2.39 (s, 1H), 2.21 (s, 1H), 2.17 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 162.34(C=O), 151.42, 144.19, 134.87, 133.75, 128.62, 125.84, 125.35 (q, J = 287.5 Hz, C-CF3), 125.03, 124.63, 118.35, 116.24, 115.17, 106.54, 77.96 (q, J = 30.0 Hz, CF3), 20.71, 12.99, 12.82. 19F NMR (376 MHz, CDCl3) δ -76.88(CF3). HRMS (APCI): m/z calculated for C18H15F3NO3 [M-H]− 350.1004, found: 350.0989.
6-Chloro-3-(1-(2,5-dimethyl-1H-pyrrol-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)-2H-chromen-2-one (3cc): Yellow solid, mp: 145.2–146.5 °C. 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.66 (s, 1H), 7.52 (dd, J = 10.9, 2.1 Hz, 2H), 7.32 (d, J = 8.6 Hz, 1H), 6.39 (s, 1H), 5.87 (s, 1H), 2.20 (s, 3H), 2.15 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 157.47(C=O), 152.62, 142.80, 132.58, 129.50, 128.95, 126.01, 125.35, 125.18 (q, J = 287.1 Hz, C-CF3), 120.93, 120.41, 118.23, 107.69, 105.86, 78.00 (q, J = 30.0 Hz, CF3), 12.95, 12.77. 19F NMR (376 MHz, CDCl3) δ -76.72(CF3). HRMS (APCI): m/z calculated for C17H12ClF3NO3 [M-H]− 370.0458, found: 370.0449.
6-Bromo-3-(1-(2,5-dimethyl-1H-pyrrol-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)-2H-chromen-2-one (3dc): Brown solid, mp: 168.6–170.4 °C. 1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.65 (dd, J = 6.7, 2.9 Hz, 3H), 7.24 (s, 1H), 6.32 (s, 1H), 5.85 (s, 1H), 2.19 (s, 3H), 2.15 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.34(C=O), 152.10, 142.81, 135.42, 131.12, 126.64, 125.86, 125.16 (q, J = 287.7 Hz, C-CF3), 124.88, 120.07, 118.28, 117.68, 114.78, 106.45, 77.97 (q, J = 30.0 Hz, CF3), 13.02, 12.82. 19F NMR (376 MHz, CDCl3) δ -76.70(CF3). HRMS (APCI): m/z calculated for C17H12BrF3NO3 [M-H]− 413.9953, found: 413.9936.
3-(1-(2,5-Dimethyl-1H-pyrrol-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)-7-methoxy-2H-chromen-2-one (3ec): Yellow solid, mp: 80.1–81.7 °C. 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.81 (s, 1H), 7.24 (m, 1H), 7.08 (s, 1H), 6.38 (s, 1H), 5.66 (s, 1H), 3.93 (s, 3H), 2.18 (s, 3H), 1.84 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.59(C=O), 147.06, 144.21, 126.74, 125.88, 125.51, 125.49 (q, J = 287.5 Hz, C-CF3), 124.90, 124.61, 123.89, 120.06, 115.11, 114.29, 106.53, 77.89 (q, J = 29.9 Hz, CF3), 56.33, 13.00, 12.82. 19F NMR (376 MHz, CDCl3) δ -76.86(CF3). HRMS (APCI): m/z calculated for C18H15F3NO4 [M-H]− 366.0953, found: 366.0941.
3-(1-(2,5-Dimethyl-1H-pyrrol-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)-8-methoxy-2H-chromen-2-one (3fc): Cyan solid, mp: 79.8–81.1 °C. 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.69 (s, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.55 (s, 1H), 5.78 (d, J = 82.7 Hz, 1H), 4.02–3.88 (m, 1H), 2.21 (s, 1H), 2.17 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 161.59(C=O), 147.06, 144.21, 125.88, 125.51, 125.49 (q, J = 287.5 Hz, C-CF3), 124.90, 124.61, 123.89, 120.06, 119.27, 115.11, 114.29, 106.53, 77.89 (q, J = 29.9 Hz, CF3), 56.33, 13.00, 12.82. 19F NMR (376 MHz, CDCl3) δ -76.86(CF3). HRMS (APCI): m/z calculated for C18H15F3NO4 [M-H]− 366.0953, found: 366.0941.
6,8-Dichloro-3-(1-(2,5-dimethyl-1H-pyrrol-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)-2H-chromen-2-one (3gc): Tawny solid, mp: 119.1–120.3 °C. 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.68-7.60 (m, 2H), 7.42 (d, J = 2.3 Hz, 1H), 6.16 (s, 1H), 5.86 (s, 1H), 2.21 (s, 3H), 2.17 (s, 3H). 13C NMR (100 MHz, CDCl3), δ 160.74(C=O), 150.72, 143.67, 133.55, 130.24, 127.58, 126.66, 125.91, 125.05 (q, J = 287.4 Hz, C-CF3), 124.67, 122.56, 120.36, 115.05, 108.26, 77.96 (q, J = 30.2 Hz, CF3), 12.98, 12.78. 19F NMR (376 MHz, CDCl3) δ -76.73(CF3). HRMS (APCI): m/z calculated for C17H11Cl2F3NO3 [M-H]− 404.0068, found: 404.0052.
6,8-Dibromo-3-(1-(2,5-dimethyl-1H-pyrrol-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)-2H-chromen-2-one (3hc): Yellow solid, mp: 172.6–174.3 °C. 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 2.1 Hz, 1H), 7.80 (s, 1H), 7.63–7.61 (m, 2H), 6.19 (s, 1H), 5.86 (s, 1H), 2.21 (s, 3H), 2.16 (s, 3H). 13C NMR (100 MHz, CDCl3), δ 160.40(C=O), 149.16, 142.67, 138.06, 129.36, 127.48, 125.53 (q, J = 287.5 Hz, C-CF3), 125.00, 120.79, 120.16, 117.60, 114.46, 111.06, 106.34, 77.91 (q, J = 30.1 Hz, CF3), 13.00, 12.80. 19F NMR (376 MHz, CDCl3) δ -77.71 (CF3). HRMS (APCI): m/z calculated for C17H11Br2F3NO2 [M-OH]+ 477.9083, found: 477.9106.
3-(1-(2,5-Dimethyl-1H-pyrrol-3-yl)-2,2,2-trifluoro-1-hydroxyethyl)-2H-benzo[h]chromen-2-one (3ic): Khaki solid, mp: 168.6–170.4 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 9.38 (s, 1H), 8.67 (d, J = 8.5 Hz, 1H), 8.49 (d, J = 9.1 Hz, 1H), 8.35 (d, J = 8.1 Hz, 1H), 8.05 (t, J = 7.7 Hz, 1H), 7.97–7.83 (m, 2H), 6.16 (s, 1H), 2.47 (s, 3H), 2.30 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.13(C=O), 153.25, 139.80, 134.20, 133.03, 130.48, 129.16, 128.63, 128.29, 127.58 (q, J = 294.1 Hz, C-CF3), 126.51, 125.94, 124.26, 121.52, 116.44, 115.18, 112.99, 106.55, 78.16 (q, J = 30.2 Hz, CF3), 13.11, 12.90. 19F NMR (376 MHz, CDCl3) δ -76.70(CF3). HRMS (APCI): m/z calculated for C21H15F3NO3 [M-H]− 386.1004, found: 386.0996.
3-(1-(4-Ethyl-3,5-dimethyl-1H-pyrrol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-2H-chromen-2-one (3ad): Yellow solid, mp: 162.9–163.5 °C. 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.85 (s, 1H), 7.65–7.56 (m, 2H), 7.38 (dd, J = 14.8, 7.6 Hz, 2H), 6.35 (s, 1H), 2.34 (q, J = 7.4 Hz, 2H), 2.19 (s, 3H), 1.83 (s, 3H), 1.02 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 161.74(C=O), 153.14, 142.61, 132.95, 129.10, 126.09, 125.27, 124.72 (q, J = 272.1 Hz, C-CF3), 123.39, 123.26, 122.46, 118.28, 118.08, 116.68, 76.68 (q, J = 30.8 Hz, CF3), 17.51, 15.56, 11.19, 10.08. 19F NMR (376 MHz, CDCl3) δ -75.42(CF3). HRMS (APCI): m/z calculated for C19H17F3NO3 [M-H]− 364.1161, found: 364.1150.
3-(1-(4-Ethyl-3,5-dimethyl-1H-pyrrol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-6-methyl-2H-chromen-2-one (3bd): Yellow solid, mp: 160.8–161.9 °C. 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.75 (s, 1H), 7.37 (m, 2H), 7.23 (d, J = 4.1 Hz, 1H), 6.39 (s, 1H), 2.42 (s, 3H), 2.36 (q, J = 7.5 Hz, 2H), 2.15 (s, 3H), 1.78 (s, 3H), 0.98 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 162.01(C=O), 151.29, 142.67, 135.15, 134.03, 128.82, 124.68 (q, J = 286.8 Hz, C-CF3), 123.18, 123.13, 122.43, 118.17, 118.04, 116.62, 116.35, 76.69 (q, J = 30.7 Hz, CF3), 20.75, 17.51, 15.57, 11.19, 10.06. 19F NMR (376 MHz, CDCl3) δ -75.46(CF3). HRMS (APCI): m/z calculated for C20H19F3NO3 [M-H]− 378.1317, found: 378.1299.
6-Chloro-3-(1-(4-ethyl-3,5-dimethyl-1H-pyrrol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-2H-chromen-2-one (3cd): Light yellow solid, mp:169.4-170.1 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.26 (s, 1H), 8.10 (d, J = 2.3 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.44 (d, J = 8.9 Hz, 1H), 6.97 (s, 1H), 2.20 (q, J = 7.3 Hz, 2H), 2.04 (s, 3H), 1.74 (s, 3H), 0.91 (d, J = 7.5 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 157.32(C=O), 152.24, 140.16, 132.55, 129.04, 128.94, 126.11, 125.42 (q, J = 287.8 Hz, C-CF3), 122.89, 121.14, 120.69, 120.03, 118.87, 118.26, 74.98 (q, J = 30.0 Hz, CF3), 17.43, 16.19, 11.09, 10.04. 19F NMR (376 MHz, DMSO-d6) δ -73.50(CF3). HRMS (APCI): m/z calculated for C19H16ClF3NO3 [M-H]− 398.0771, found: 398.0751.
6-Bromo-3-(1-(4-ethyl-3,5-dimethyl-1H-pyrrol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-2H-chromen-2-one (3dd): Yellow solid, mp: 168.6–169.2 °C. 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.77–7.67 (m, 2H), 7.27 (d, J = 9.6 Hz, 1H), 6.14 (s, 1H), 2.33 (q, J = 7.6 Hz, 2H), 2.18 (s, 3H), 1.81 (s, 3H), 1.01 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 160.99 (C=O), 151.97, 141.31, 135.69, 131.29, 124.67, 124.51 (q, J = 286.8 Hz, C-CF3), 123.48, 122.54, 119.76, 118.36, 117.90, 117.71, 116.77, 76.66 (q, J = 30.9 Hz, CF3), 17.49, 15.55, 11.20, 10.08. 19F NMR (376 MHz, CDCl3) δ -75.34(CF3). HRMS (APCI): m/z calculated for C19H16BrF3NO3 [M-H]− 442.0266, found: 442.0243.
3-(1-(4-Ethyl-3,5-dimethyl-1H-pyrrol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-7-methoxy-2H-chromen-2-one (3ed): Cyan solid, mp: 160.4–161.1 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.18 (s, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.03–6.97 (m, 2H), 6.79 (s, 1H), 3.86 (s, 3H), 2.25–2.19 (m, 2H), 2.06 (s, 3H), 1.74 (s, 3H), 0.93 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 163.39(C=O), 158.27, 155.58, 141.29, 131.12, 125.63 (d, J = 290.7 Hz, C-CF3), 122.61, 121.36, 120.53, 119.44, 114.52, 113.20, 112.15, 100.56, 74.99 (d, J = 29.0 Hz, CF3), 56.50, 17.50, 16.24, 11.14, 10.10. 19F NMR (376 MHz, DMSO-d6) δ -75.42(CF3). HRMS (APCI): m/z calculated for C20H19F3NO4 [M-H]− 394.1266, found: 394.1247.
6,8-Dichloro-3-(1-(4-ethyl-3,5-dimethyl-1H-pyrrol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-2H-chromen-2-one (3gd): Dark yellow solid, mp: 145.8–146.5 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.33 (s, 1H), 8.17 (d, J = 2.3 Hz, 1H), 8.00 (d, J = 2.3 Hz, 1H), 7.04 (s, 1H), 2.23 (q, J = 7.4 Hz, 2H), 2.06 (s, 3H), 1.80 (s, 3H), 0.93 (d, J = 7.5 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 156.23(C=O), 148.16, 140.16, 131.95, 128.85, 128.31, 126.98, 125.38 (q, J = 287.6 Hz, C-CF3), 122.98, 121.15, 120.88, 118.73, 115.10, 74.95 (q, J = 29.7 Hz, CF3), 17.45, 16.20, 11.13, 11.09, 10.14. 19F NMR (376 MHz, DMSO-d6) δ -73.30. HRMS (APCI): m/z calculated for C19H15Cl2F3NO3 [M-H]− 432.0381, found: 432.0357.
6,8-Dibromo-3-(1-(4-ethyl-3,5-dimethyl-1H-pyrrol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-2H-chromen-2-one (3hd): Dark yellow solid, mp: 142.2–142.9 °C.1H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.65 (s, 1H), 7.60 (d, J = 2.2 Hz, 1H), 5.88 (s, 1H), 2.29–2.23 (m, 2H), 2.11 (s, 3H), 1.74 (s, 3H), 0.95 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 156.40(C=O), 149.64, 140.11, 137.24, 131.84, 126.84, 122.97, 122.54 (q, J = 287.5 Hz, C-CF3), 120.69, 118.75, 116.78, 115.09, 110.16, 74.94 (q, J = 29.8 Hz, CF3), 17.46, 16.21, 11.13, 11.09, 10.15. 19F NMR (376 MHz, DMSO-d6) δ -73.32(CF3). HRMS (APCI): m/z calculated for C19H15Br2F3NO3 [M-H]− 521.9350, found: 521.9319.
3-(2,2,2-Trifluoro-1-hydroxy-1-(1H-pyrrol-2-yl)-ethyl)-2H-chromen-2-one (3ae): White solid, mp: 153.5-154.3 °C. 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 7.84 (s, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.50 (s, 1H), 7.44–7.34 (m, 3H), 7.26 (s, 1H), 6.86 (s, 1H), 6.40 (s, 1H), 6.27 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 162.44(C=O), 154.19, 146.88, 135.26, 129.13, 125.89, 125.20, 124.45 (q, J = 286.5 Hz, C-CF3), 118.81, 118.33, 116.62 110.00, 109.06, 108.40, 76.69 (q, J = 31.4 Hz, CF3). 19F NMR (376 MHz, CDCl3) δ -78.07(CF3). HRMS (APCI): m/z calculated for C15H9F3NO2 [M-H]− 308.0540, found: 308.0537.
3-(2,2,2-Trifluoro-1-hydroxy-1-(1-methyl-1H-pyrrol-2-yl)ethyl)-2H-chromen-2-one (3af): White solid, mp: 129.3-131.1 °C. 1H NMR (400 MHz, CDCl3) δ 7.66–7.60 (m, 1H), 7.46–7.40 (m, 2H), 7.36–7.31 (m, 2H), 7.21 (s, 1H), 6.70–6.64 (m, 1H), 6.46 (s, 1H), 6.17–6.10 (m, 1H), 3.55 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.22 (C=O), 153.42, 146.17, 133.39, 129.06, 125.76, 125.35, 124.87, 124.71 (q, J = 287.8 Hz, C-CF3), 122.31, 118.39, 116.69, 111.43, 106.56, 77.85 (q, J = 30.6 Hz, CF3), 36.14. 19F NMR (376 MHz, CDCl3) δ -77.07(CF3). HRMS (APCI): m/z calculated for C16H11F3NO2 [M-OH]+ 306.0737, found: 306.0747.

3.2. In Vitro Antifungal Assay

Antifungal assays were performed against F. graminearum (from corn), F. oxysporum, F. graminearum (from wheat), F. moniliforme, R. solani Kuhn, and P. parasitica var nicotianae in vitro by the plate growth rate method. The synthesized compounds were dissolved in 2% DMSO to yield a 10 mg/mL stock solution. Then, each solution was added to sterile potato dextrose agar (PDA) to give final concentrations of 0.1 mg/mL. After the mixture was chilled, the mycelium of the fungi was transferred to the test plate and incubated at 26 °C. When the mycelium of the fungi reached the edges of the control plate (without sample), the inhibitory index was calculated as follows: Inhibitory index (%) = (Db − Da)/(Db − Dc) × 100%, where Da is the colony diameter of the growth zone in the test plate, Db is the colony diameter of the growth zone in the control plate, and Dc is the diameter of the mycelial disc. The median effective concentration (EC50) of each compound with a significant fungicidal activity was further evaluated in three independent experiments. The statistical analyses were performed using SPSS software (IBM SPSS Statistic 26).

3.3. Molecular Docking

The molecular docking studies of compound 3cd and triadimefon were performed with the assistance of Discovery Studio 2016 software and pymol. The crystal structure of Tre was acquired from the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB code 2JF4). The ligand validoxylamine was extracted, and all water molecules were eliminated from this crystal complex. Libdock was applied for simulating and evaluating the interactions between the compounds and the target protein by an empirical scoring function.

4. Conclusions

In conclusion, we have developed a new and practical catalyst-free method for novel α-trifluoromethylated tertiary alcohols bearing coumarins at ambient temperature. This procedure means a promising approach for attaining these new heterocycles, since it applies mild and easily operational conditions (no special reagents, catalysts, or additives). Altogether, 29 new α-trifluoromethylated tertiary alcohols were synthesized in high to excellent yields. The crystal structure of compound 3fa was studied by single-crystal XRD analysis. The biological activity of the α-trifluoromethylated tertiary alcohols was also tested in in vitro antifungal assays. The bioassay results indicated that the compounds showed broad-spectrum fungicidal activity in vitro.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28010260/s1, Figure S1: Molecular packing of compound 3fa (CCDC 2167896); Table S1: The refinement information and crystallographic data of 3fa; and Figures S2–S88: 1H-NMR, 13C-NMR and 19F-NMR spectra of compounds 3aa–3fa. Figures S89–S117: HRMS spectra of compounds 3aa–3fa.

Author Contributions

Conceptualization, S.J., L.W. and C.X.; Data curation, S.J.; Formal analysis, L.S.; Investigation, S.J., X.C., B.Z. and M.X.; Methodology, G.Y. and L.W.; Project administration, C.W.; Resources, C.X.; Supervision, L.F. and Z.P.; Writing—original draft, L.W.; Writing—review & editing, G.Y., L.W. and C.X. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Natural Science Foundation of Henan Province (222300420459(to C.X.), 222300420456(to G.Y.)), Science and Technology Agency of Henan Province (212102311067(to L.W.), 222102310243(to C.W.)), and Science and Technology Innovation Fund of Henan Agricultural University (KJCX2020A19(to L.W.)).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Shimizu, M.; Hiyama, T. Modern Synthetic Methods for Fluorine-Substituted Target Molecules. Angew. Chem. Int. Ed. 2005, 44, 214–231. [Google Scholar] [CrossRef]
  2. Ma, J.; Cahard, D. Strategies for nucleophilic, electrophilic, and radical trifluoromethylations. J. Fluor. Chem. 2007, 128, 975–996. [Google Scholar] [CrossRef]
  3. Hagmann, W.K. The Many Roles for Fluorine in Medicinal Chemistry. J. Med. Chem. 2008, 51, 4359–4369. [Google Scholar] [CrossRef] [PubMed]
  4. Zheng, Y.; Ma, J.-A. Combination Catalysis in Enantioselective Trifluoromethylation. Adv. Synth. Catal. 2010, 352, 2745–2750. [Google Scholar] [CrossRef]
  5. Liu, X.; Xu, C.; Wang, M.; Liu, Q. Trifluoromethyltrimethylsilane: Nucleophilic Trifluoromethylation and Beyond. Chem. Rev. 2015, 115, 683–730. [Google Scholar] [CrossRef] [PubMed]
  6. Corbett, J.W.; Soo, S.K.; James, D.R.; Lisa, A.G.; Nicholas, A.M.; Lee, T.B.; Sharon, D.; Susan, J.; Ronald, M.K.; Beverly, C.C.; et al. Inhibition of clinically relevant mutant variants of HIV-1 by quinazolinone non-nucleoside reverse transcriptase inhibitors. J. Med. Chem. 2000, 43, 2019–2030. [Google Scholar] [CrossRef] [PubMed]
  7. Sani, M.; Belotti, D.; Giavazzi, R.; Panzeri, W.; Volonterio, A.; Zanda, M. Synthesis and evaluation of stereopure α-trifluoromethyl-malic hydroxamates as inhibitors of matrix metalloproteinases. Tetrahedron Lett. 2004, 45, 1611–1615. [Google Scholar] [CrossRef]
  8. Betageri, R.; Zhang, Y.; Zindell, R.M.; Kuzmich, D.; Kirrane, T.M.; Bentzien, J.; Cardozo, M.; Capolino, A.J.; Fadra, T.N.; Nelson, R.M.; et al. Trifluoromethyl group as a pharmacophore: Effect of replacing a CF3 group on binding and agonist activity of a glucocorticoid receptor ligand. Bioorg. Med. Chem. Lett. 2005, 15, 4761–4769. [Google Scholar] [CrossRef]
  9. Caron, S.; Do, N.M.; Sieser, J.E.; Arpin, P.; Vazquez, E. Process Research and Development of an NK-1 Receptor Antagonist. Enantioselective Trifluoromethyl Addition to a Ketone in the Preparation of a Chiral Isochroman. Org. Process Res. Dev. 2007, 11, 1015–1024. [Google Scholar] [CrossRef]
  10. Han, X.; Ouyang, W.; Liu, B.; Wang, W.; Tien, P.; Wu, S.; Zhou, H.-B. Enantioselective inhibition of reverse transcriptase (RT) of HIV-1 by non-racemic indole-based trifluoropropanoates developed by asymmetric catalysis using recyclable organocatalysts. Org. Biomol. Chem. 2013, 11, 8463–8475. [Google Scholar] [CrossRef]
  11. Jiang, H.-X.; Zhuang, D.; Huang, Y.; Cao, X.-X.; Yao, J.-H.; Li, J.-Y.; Wang, J.-Y.; Zhang, C.; Jiang, B. Design, synthesis, and biological evaluation of novel trifluoromethyl indole derivatives as potent HIV-1 non-nucleoside reverse transcriptase inhibitors with an improved drug resistance profile. Org. Biomol. Chem. 2014, 12, 3446–3458. [Google Scholar]
  12. Wang, J.; Sánchez-Roselló, M.; Aceña, J.L.; del Pozo, C.; Sorochinsky, A.E.; Fustero, S.; Soloshonok, V.A.; Liu, H. Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001–2011). Chem. Rev. 2014, 114, 2432–2506. [Google Scholar] [CrossRef] [PubMed]
  13. Inoue, M.; Sumii, Y.; Shibata, N. Contribution of Organofluorine Compounds to Pharmaceuticals. ACS Omega 2020, 5, 10633–10640. [Google Scholar] [CrossRef]
  14. Aikawa, K.; Hioki, Y.; Mikami, K. Highly enantioselective alkynylation of trifluoropyruvate with alkynylsilanes catalyzed by the BINAP-Pd complex: Access to r-trifluoromethyl-substituted tertiary alcohols. Org. Lett. 2010, 12, 5716–5719. [Google Scholar] [CrossRef] [PubMed]
  15. Lutete, L.M.; Miyamoto, T.; Ikemoto, T. Tertiary amino thiourea-catalyzed asymmetric cross aldol reaction of aryl methyl ketones with aryl trifluoromethyl ketones. Tetrahedron Lett. 2016, 57, 1220–1223. [Google Scholar] [CrossRef]
  16. Wang, P.; Li, H.-F.; Zhao, J.-Z.; Du, Z.-H.; Da, C.-S. Organocatalytic Enantioselective Cross-Aldol Reaction of o-Hydroxyarylketones and Trifluoromethyl Ketones. Org. Lett. 2017, 19, 2634–2637. [Google Scholar] [CrossRef] [PubMed]
  17. Wang, W.; Xiong, W.; Wang, J.; Wang, Q.-A.; Yang, W. Brønsted Acid-Catalyzed Asymmetric Friedel–Crafts Alkylation of Indoles with Benzothiazole-Bearing Trifluoromethyl Ketone Hydrates. J. Org. Chem. 2020, 85, 4398–4407. [Google Scholar] [CrossRef]
  18. Carceller-Ferrer, L.; del Campo, A.G.; Vila, C.; Blay, G.; Muñoz, M.C.; Pedro, J.R. Catalytic Diastereo- and Enantioselective Synthesis of Tertiary Trifluoromethyl Carbinols through a Vinylogous Aldol Reaction of Alkylidenepyrazolones with Trifluoromethyl Ketones. J. Org. Chem. 2022, 87, 4538–4549. [Google Scholar] [CrossRef]
  19. Blay, G.; Fernández, I.; Monleón, A.; Pedro, J.R.; Vila, C. Enantioselective Zirconium-Catalyzed Friedel−Crafts Alkylation of Pyrrole with Trifluoromethyl Ketones. Org. Lett. 2009, 11, 441–444. [Google Scholar] [CrossRef]
  20. Kashikura, W.; Itoh, J.; Mori, K.; Akiyama, T. Enantioselective Friedel-Crafts Alkylation of Indoles, Pyrroles, and Furans with Trifluoropyruvate Catalyzed by Chiral Phosphoric Acid. Chem. Asian J. 2010, 5, 470–472. [Google Scholar] [CrossRef]
  21. Le, T.P.; Higashita, K.; Tanaka, S.; Yoshimura, M.; Kitamura, M. Revisiting the CuII-Catalyzed Asymmetric Friedel–Crafts Reaction of Indole with Trifluoropyruvate. Org. Lett. 2018, 20, 7149–7153. [Google Scholar] [CrossRef] [PubMed]
  22. Cai, L.; Zhao, Y.; Huang, T.; Meng, S.; Jia, X.; Chan, A.S.C.; Zhao, J. Chiral Phosphoric-Acid-Catalyzed Regioselective and Enantioselective C7-Friedel–Crafts Alkylation of 4-Aminoindoles with Trifluoromethyl Ketones. Org. Lett. 2019, 21, 3538–3542. [Google Scholar] [CrossRef] [PubMed]
  23. Kasztelan, A.; Biedrzycki, M.; Kwiatkowski, P. High-Pressure-Mediated Asymmetric Organocatalytic Hydroxyalkylation of Indoles with Trifluoromethyl Ketones. Adv. Synth. Catal. 2016, 358, 2962–2969. [Google Scholar] [CrossRef]
  24. Biedrzycki, M.; Kasztelan, A.; Kwiatkowski, P. High-Pressure Accelerated Enantioselective Addition of Indoles to Trifluoromethyl Ketones with a Low Loading of Chiral BINOL-Derived Phosphoric Acid. ChemCatChem 2017, 9, 2453–2456. [Google Scholar] [CrossRef]
  25. Hua, Y.-Z.; Chen, J.-W.; Yang, H.; Wang, M.-C. Asymmetric Friedel–Crafts Alkylation of Indoles with Trifluoromethyl Pyruvate Catalyzed by a Dinuclear Zinc Catalyst. J. Org. Chem. 2018, 83, 1160–1166. [Google Scholar] [CrossRef]
  26. Sasaki, S.; Yamauchi, T.; Higashiyama, K. Dy(OTf)3/Pybox-catalyzed enantioselective Friedel–Crafts alkylation of indoles with α,β-unsaturated trifluoromethyl ketones. Tetrahedron Lett. 2010, 51, 2326–2328. [Google Scholar] [CrossRef]
  27. Anokhin, M.V.; Feofanov, M.N.; Averin, A.D.; Beletskaya, I.P. The asymmetric Friedel-Crafts reaction of indoles with arylidenemalonates catalyzed by MgI2/PyBox complexes. ChemistrySelect 2018, 3, 1388–1391. [Google Scholar] [CrossRef]
  28. Young, C.M.; Taylor, J.E.; Smith, A.D. Evaluating aryl esters as bench-stable C(1)-ammonium enolate precursors in catalytic, enantioselective Michael addition–lactonisations. Org. Biomol. Chem. 2019, 17, 4747–4752. [Google Scholar] [CrossRef]
  29. Zhao, H.-C.; Zhang, Z.-B.; Lu, W.-H.; Han, P.; Wang, W.; Jing, L.-H. 3-Carboxamide oxindoles as 1,3-C,N-bisnucleophiles for the highly diastereoselective synthesis of CF3-containing spiro-δ-lactam oxindoles featuring acyl at the ortho-position of spiro carbon atom. Tetrahedron Lett. 2021, 83, 153426. [Google Scholar] [CrossRef]
  30. Bao, J.-P.; Xu, C.-L.; Yang, G.-Y.; Wang, C.-X.; Zheng, X.; Yuan, X.-X. Novel 6a,12b-dihydro-6H,7H-chromeno [3,4-c] chromen-6-ones: Synthesis, structure and antifungal activity. Molecules 2019, 24, 1745. [Google Scholar] [CrossRef] [Green Version]
  31. Yuan, X.; Wu, L.; Xu, C.; Pan, Z.; Shi, L.; Yang, G.; Wang, C.; Fan, S. A consecutive one-pot two-step approach to novel trifluoromethyl-substituted bis(indolyl)methane derivatives promoted by Sc(OTf)3 and p-TSA. Tetrahedron Lett. 2019, 60, 151329. [Google Scholar] [CrossRef]
  32. Shi, L.-J.; Liu, Y.; Wang, C.-X.; Yuan, X.-X.; Liu, X.; Wu, L.-L.; Pan, Z.-L.; Yu, Q.; Xu, C.-L.; Yang, G.-Y. Synthesis of 1-(beta-coumarinyl)-1-(beta-indolyl)trifluoroethanols through regioselective Friedel-Crafts alkylation of indoles with beta-(trifluoroacetyl)coumarins catalyzed by Sc(OTf)3. RSC Adv. 2020, 10, 13929–13935. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Yang, G.; Shi, L.; Pan, Z.; Wu, L.; Fan, L.; Wang, C.; Xu, C.; Liang, J. The synthesis of coumarin thiazoles containing a trifluoromethyl group and their antifungal activities. Arab. J. Chem. 2021, 14, 102880. [Google Scholar] [CrossRef]
  34. Wu, L.; Yuan, X.; Yang, G.; Xu, C.; Pan, Z.; Shi, L.; Wang, C.; Fan, L. An eco-friendly procedure for the synthesis of new phosphates using KF/Al2O3 under solventless conditions and their antifungal properties. J. Saudi Chem. Soc. 2021, 25, 101273. [Google Scholar] [CrossRef]
  35. Wang, X.; Bastow, K.F.; Sun, C.-M.; Lin, Y.-L.; Yu, H.-J.; Don, M.-J.; Wu, T.-S.; Nakamura, S.; Lee, K.-H. Antitumor Agents. Part 239. Isolation, Structure Elucidation, Total Synthesis, and anti-Breast Cancer Activity of Neo-tanshinlactone from Salvia miltiorrhiza. J. Med. Chem. 2004, 47, 5816–5819. [Google Scholar] [CrossRef]
  36. Olmedo, D.; Sancho, R.; Bedoya, L.M.; López-Pérez, J.L.; DEL Olmo, L.M.B.; Muñoz, E.; Alcamí, J.; Gupta, M.P.; Feliciano, A.S. 3-Phenylcoumarins as Inhibitors of HIV-1 Replication. Molecules 2012, 17, 9245–9257. [Google Scholar] [CrossRef]
  37. Matos, M.J.; Vazquez-Rodriguez, S.; Santana, L.; Uriarte, E.; Fuentes-Edfuf, C.; Santos, Y.; Muñoz-Crego, A. Synthesis and structure-activity relationships of novel amino/nitro substituted 3-arylcoumarins as antibacterial agents. Molecules 2013, 18, 1394–1404. [Google Scholar] [CrossRef] [Green Version]
  38. Ahmad, I.; Thakur, J.P.; Chanda, D.; Saikia, D.; Khan, F.; Dixit, S.; Kumar, A.; Konwar, R.; Negi, A.S.; Gupta, A. Syntheses of lipophilic chalcones and their conformationally restricted analogues as antitubercular agents. Bioorg. Med. Chem. Lett. 2013, 23, 1322–1325. [Google Scholar] [CrossRef]
  39. Hanke, S.; Tindall, C.A.; Pippel, J.; Ulbricht, D.; Pirotte, B.; Ravaux, M.R.; Heiker, J.T.; Sträter, N. Structural Studies on the Inhibitory Binding Mode of Aromatic Coumarinic Esters to Human Kallikrein-Related Peptidase 7. J. Med. Chem. 2020, 63, 5723–5733. [Google Scholar] [CrossRef]
  40. Wei, L.; Hou, T.; Li, J.; Zhang, X.; Zhou, H.; Wang, Z.; Cheng, J.; Xiang, K.; Wang, J.; Zhao, Y.; et al. Structure–Activity Relationship Studies of Coumarin-like Diacid Derivatives as Human G Protein-Coupled Receptor-35 (hGPR35) Agonists and a Consequent New Design Principle. J. Med. Chem. 2021, 64, 2634–2647. [Google Scholar] [CrossRef]
  41. Yan, N.L.; Santos-Martins, D.; Nair, R.; Chu, A.; Wilson, I.A.; Johnson, K.A.; Forli, S.; Morgan, G.J.; Petrassi, H.M.; Kelly, J.W. Discovery of Potent Coumarin-Based Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains Using Structure-Based Design. J. Med. Chem. 2021, 64, 6273–6299. [Google Scholar] [CrossRef] [PubMed]
  42. Tao, M.; Wang, A.; Guo, P.; Li, W.; Zhao, L.; Tong, J.; Wang, H.; Yu, Y.; He, C. Visible-Light-Induced Regioselective Deaminative Alkylation of Coumarins via Photoredox Catalysis. Adv. Synth. Catal. 2021, 364, 24–29. [Google Scholar] [CrossRef]
  43. Zhang, J.; Han, Q.; Jiang, Z.; Li, H.; Deng, M.; Zhu, K.; Li, M.; Duan, H. Chitinase inhibitors and synthesis and agricultural bioactivity of thiazolidinones: A review. Chin. J. Pest. Sci. 2021, 23, 421–437. [Google Scholar]
Molecules 28 00260 g001 550
Figure 1. Examples of pharmaceuticals containing α-trifluoromethylated tertiary alcohol motifs.
Figure 1. Examples of pharmaceuticals containing α-trifluoromethylated tertiary alcohol motifs.
Molecules 28 00260 g001
Molecules 28 00260 g002 550
Figure 2. Friedel–Crafts alkylation of indole or pyrrole and trifluoromethylketone or α,β-unsaturated trifluoromethyl ketone.
Figure 2. Friedel–Crafts alkylation of indole or pyrrole and trifluoromethylketone or α,β-unsaturated trifluoromethyl ketone.
Molecules 28 00260 g002
Molecules 28 00260 sch001 550
Scheme 1. Scaled-up experiment of the one-pot reaction.
Scheme 1. Scaled-up experiment of the one-pot reaction.
Molecules 28 00260 sch001
Molecules 28 00260 g003 550
Figure 3. X-ray crystal structure of compound 3fa (CCDC 2167896).
Figure 3. X-ray crystal structure of compound 3fa (CCDC 2167896).
Molecules 28 00260 g003
Molecules 28 00260 g004a 550Molecules 28 00260 g004b 550
Figure 4. Docking modes of 3cd (A) and inhibitor argifin (B) with 1W9U.
Figure 4. Docking modes of 3cd (A) and inhibitor argifin (B) with 1W9U.
Molecules 28 00260 g004aMolecules 28 00260 g004b
Table
Table 1. Optimization of the reaction 3-(trifluoroacetyl)coumarin 1a and 2-methylpyrrole 2a a.
Table 1. Optimization of the reaction 3-(trifluoroacetyl)coumarin 1a and 2-methylpyrrole 2a a.
Molecules 28 00260 i001
EntryCatalystSolventTemp. (℃) Yield (%) b
1AlCl3 (5%)CH2Cl22546
2FeCl3 (5%)CH2Cl22539
3CuCl2 (5%)CH2Cl22541
4CH3COOAg (5%)CH2Cl22540
5Sc(OTf)3 (5%)CH2Cl22520
6Cu(OTf)2 (5%)CH2Cl22546
7—CH2Cl22597
8—CHCl32548
9—EtOAc2520
10—CH3CN2535
11—toluene2521
12—THF2536
13—dioxane2555
14—ClCH2CH2Cl2578
15—BrCH2CH2Br2568
16—CH2Cl2036
a Reactions were performed with 1a (1.0 mmol) and 2a (1.0 mmol), with catalyst (1%) or without catalyst in the solvent (1.5 mL). b Isolated yield.
Table
Table 2. Reaction scope of the Friedel–Crafts reaction of 3-(trifluoroacetyl)coumarin 1 with pyrroles 2 a.
Table 2. Reaction scope of the Friedel–Crafts reaction of 3-(trifluoroacetyl)coumarin 1 with pyrroles 2 a.
Molecules 28 00260 i002
EntryR1R2R3ProductYield b
1H2-MeH3aa97
26-Me2-MeH3ba85
36-Cl2-MeH3ca91
46-Br2-MeH3da84
57-OMe2-MeH3ea97
68-OMe2-MeH3fa85
76,8-(Cl)22-MeH3ga95
86,8-(Br)22-MeH3ha90
9naphthyl2-MeH3ia89
10H2,4-(Me)2H3ab93
118-OMe2,4-(Me)2H3fb84
12 cH2,5-(Me)2H3ac78
13 c6-Me2,5-(Me)2H3bc85
14 c6-Cl2,5-(Me)2H3cc88
15 c6-Br2,5-(Me)2H3dc86
16 c7-OMe2,5-(Me)2H3ec91
17 c8-OMe2,5-(Me)2H3fc85
18 c6,8-(Cl)22,5-(Me)2H3gc90
19 c6,8-(Br)22,5-(Me)2H3hc87
20 cnaphthyl2,5-(Me)2H3ic82
21H2,4-(Me)2-3-EtH3ad92
226-Me2,4-(Me)2-3-EtH3bd89
236-Cl2,4-(Me)2-3-EtH3cd92
246-Br2,4-(Me)2-3-EtH3dd87
257-OMe2,4-(Me)2-3-EtH3ed92
266,8-(Cl)22,4-(Me)2-3-EtH3gd86
276,8-(Br)22,4-(Me)2-3-EtH3hd75
28HHH3ae77
29HHMe3af73
30H2-COOHH—NR d
a Reactions were performed with 1a (1.0 mmol) and 2a (1.0 mmol) in the CH2Cl2 (10 mL). b Isolated yield. c The reaction was performed with Sc(OTf)3 (5%) at 45 ℃. d NR=No reaction.
Table
Table 3. In Vitro Fungicidal Activity of Target Compounds against Phytopathogens a–c.
Table 3. In Vitro Fungicidal Activity of Target Compounds against Phytopathogens a–c.
CompoundABCDEF
3aa31 ± 024 ± 0<1026 ± 364 ± 117 ± 1
3ba25 ± 328 ± 0<1019 ± 258 ± 215 ± 0
3ca<10<10<1016 ± 144 ± 1<10
3da20 ± 121 ± 0<1014 ± 054 ± 1<10
3ea27 ± 124 ± 1<1014 ± 047 ± 021 ± 0
3fa<10<10<10<1050 ± 1<10
3ga37 ± 273 ± 1<1022 ± 154 ± 021 ± 1
3ha59 ± 236 ± 1<1055 ± 164 ± 079 ± 0
3ia20 ± 017 ± 0<1029 ± 053 ± 143 ± 1
3ab75 ± 367 ± 145 ± 274 ± 086 ± 264 ± 0
3ac77 ± 0<10<1077 ± 054 ± 182 ± 1
3bc36 ± 148 ± 1<1040 ± 247 ± 020 ± 0
3cc47 ± 356 ± 1<1055 ± 170 ± 061 ± 1
3dc34 ± 042 ± 0<1046 ± 161 ± 129 ± 1
3ec40 ± 049 ± 028 ± 051 ± 058 ± 040 ± 1
3fc53 ± 245 ± 024 ± 046 ± 049 ± 045 ± 1
3gc64 ± 156 ± 047 ± 056 ± 080 ± 250 ± 2
3hc60 ± 250 ± 045 ± 143 ± 160 ± 132 ± 0
3ic28 ± 124 ± 020 ± 033 ± 154 ± 115 ± 1
3ad97 ± 084 ± 287 ± 082 ± 098 ± 188 ± 1
3bd95 ± 088 ± 086 ± 162 ± 178 ± 285 ± 1
3cd94 ± 269 ± 176 ± 162 ± 186 ± 157 ± 1
3dd76 ± 258 ± 135 ± 147 ± 354 ± 135 ± 3
3ed64 ± 273 ± 171 ± 152 ± 174 ± 133 ± 1
3gd87 ± 293 ± 162 ± 294 ± 110087 ± 1
3hd89 ± 284 ± 153 ± 155 ± 010088 ± 1
triadimefon45 ± 141 ± 125 ± 185 ± 170 ± 130 ± 1
a A: Fusarium graminearum (from corn), B: Fusarium oxysporum, C: Fusarium graminearum (from wheat), D: Fusarium moniliforme, E: Rhizoctonia solani Kuhn, F: Phytophthora parasitica var nicotianae. b Values are means of three replicates. c The compounds exhibited a certain degree of fungicidal activity at a concentration of 500 μg/mL.
Table
Table 4. In Vitro Potency (EC50) of Compounds with Higher Preliminary Activities a.
Table 4. In Vitro Potency (EC50) of Compounds with Higher Preliminary Activities a.
FungicidalCompoundRegression EquationR2EC50 (μg/mL)
F. graminearum3ady = 0.401x + 1.0070.94154.4
3bdy = 0.445x + 0.9300.930107.8
triadimefony = 0.346x + 1.1810.97410.7
F. oxysporum3hdy = 0.434x + 0.9410.94796.7
triadimefony = 0.498x + 1.1810.99042.9
F. moniliforme3gdy = 0.654x + 1.1820.93790.9
triadimefony = 0.234x + 1.1940.9771.1
R. solani Kuhn.3ady = 0.317x + 1.0320.97121.0
3cdy = 0.226x + 0.9440.98510.9
3gdy = 0.321x + 1.0650.97917.4
3hdy = 0.339x + 1.0750.99320.2
triadimefony = 0.329x + 1.2270.9746.1
P. parasitica var nicotianae3gdy = 0.616x + 1.0740.994117.0
3hdy = 0.440x + 1.0270.96463.4
triadimefony = 0.248x + 0.7450.984102.3
a Values are means of three replicates.
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Jiang, S.; Yang, G.; Shi, L.; Fan, L.; Pan, Z.; Wang, C.; Chang, X.; Zhou, B.; Xu, M.; Wu, L.; et al. Design, Catalyst-Free Synthesis of New Novel α-Trifluoromethylated Tertiary Alcohols Bearing Coumarins as Potential Antifungal Agents. Molecules 2023, 28, 260. https://doi.org/10.3390/molecules28010260

AMA Style

Jiang S, Yang G, Shi L, Fan L, Pan Z, Wang C, Chang X, Zhou B, Xu M, Wu L, et al. Design, Catalyst-Free Synthesis of New Novel α-Trifluoromethylated Tertiary Alcohols Bearing Coumarins as Potential Antifungal Agents. Molecules. 2023; 28(1):260. https://doi.org/10.3390/molecules28010260

Chicago/Turabian Style

Jiang, Shengfei, Guoyu Yang, Lijun Shi, Liangxin Fan, Zhenliang Pan, Caixia Wang, Xiaodan Chang, Bingyi Zhou, Meng Xu, Lulu Wu, and et al. 2023. "Design, Catalyst-Free Synthesis of New Novel α-Trifluoromethylated Tertiary Alcohols Bearing Coumarins as Potential Antifungal Agents" Molecules 28, no. 1: 260. https://doi.org/10.3390/molecules28010260

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