Highly Chemoselective Synthesis of Azaarene-Equipped CF3-Tertiary Alcohols under Metal-Free Conditions and Their Fungicidal Activities

A highly chemoselective reaction between α,β-unsaturated trifluoromethyl ketones with azaarenes under metal-free conditions was carried out, affording a range of valuable azaarene-equipped CF3-tertiary alcohols in moderate to excellent yields (up to 95% yield) with good tolerance of functional groups, and their structures were confirmed by NMR, HRMS, and X-ray diffraction for validation. This method features simple reaction conditions (only solvent), high atom- and step-economy, and broad substrate scope. Moreover, most of the target products exhibited promising fungicidal activities, and compound 3al exhibited 91.65% fungicidal activity against R. solani, with an EC50 value of 0.18 mg/mL.


■ INTRODUCTION
Fluorine-containing molecules are pervasive motifs, and they exhibit broad applications in the field of medicines, agrochemicals, polymers, functional materials, and other chemical industries, owing to the specific characteristics of the fluorine atom, such as high electronegativity, high lipophilicity, good hydrophobicity, metabolic stability, and bioavailability. 1 Particularly, trifluoromethyl-substituted tertiary alcohols are embedded in a range of pharmaceuticals. 2,3 For example, compounds A and C are glucorticoid receptor agonists, 4 compound B is a reverse transcriptase inhibitor of HIV, 5 compound D is a sleep inducer, 6 compound E is an antiinflammatory reagent, 7 and compound F is a cholesteryl ester transfer protein inhibitor 8 (Scheme 1). Therefore, the synthesis of these skeletons is highly attractive and a plethora of practical protocols for rapid assembly of CF 3 -substituted tertiary alcohols have been developed in recent years.
On the other hand, the direct functionalization of ubiquitous inert C−H bonds has been rapidly developed in past decades, owing to the advantages in terms of atom-and step-economy. 9 In this regard, C(sp 3 )−H functionalization of azaarenes has emerged as a powerful method for the rapid assembly of functional N-heterocycle molecules, which are pervasive motifs found in a series of pharmaceuticals, natural products, and materials. 10 However, C(sp 3 )−H functionalization of methylquinoline and its derivatives coupled with trifluoromethyl ketones to construct CF 3 -tertiary alcohols have been less explored, and Lewis acid is often required (Scheme 2a). 11,12 Thus, further development of new efficient functional transformations from the point of more sustainable and environmental chemistry is extremely valuable. 13 In this context, with our ongoing interest in C−H activation and CF 3 -functionalization chemistry, 14 we present a novel CF 3tertiary alcohol synthesis protocol of trifluoromethyl ketones with azaarenes under metal-free conditions, thus resulting in various ubiquitous CF 3 -tertiary alcohols, which are frequently found in pharmaceutical chemistry (Scheme 2b). 2

■ RESULTS AND DISCUSSION
To validate our hypothesis, we began our studies by employing β-(trifluoroacetyl)coumarin 1a and 2-methylquinoline 2a as model substrates to explore the reaction conditions, and the results are summarized in Table 1. Initially, a comprehensive screening of reaction solvents was carried out (entries 1−11). To our delight, all the cases such as DMF, DMSO, EtOH, acetone, EA, DCE, CH 3 CN, 1,4-dioxane, toluene, THF, and nhexane were feasible to perform the titled conversion, as shown in Scheme 2, and the CH 3 CN solvent was identified as the best choice, affording anticipated product 3aa in 82% yield (entry 7). Further adjusting the reaction temperature, neither increase nor decrease had a positive effect (entries 12−13). Gratifyingly, it was found that the ratio of two substrates could affect the reaction performance dramatically (entries 14−15), improving the yield of 3aa to 93% when altering the ratio of 1a:2a to 1:2 (entry 15). Additionally, the potential 1,4addition byproduct was not discovered during the whole optimization reaction conditions. Accordingly, the optimized reaction conditions were determined as follows: 1a (0.2 mmol), 2a (0.4 mmol), and CH 3 CN (2.0 mL) at 90°C under an air atmosphere for 9 h.
With efficient protocols in hand, the scope with respect to the azaarenes was first examined. The results indicated that various azaarenes are well tolerated, and the reaction of azaarenes 2b-r with 1a underwent the envisioned pathways to deliver the CF 3 -tertiary alcohols 3ab-ar in 41−93% yields ( Table 2). For instance, diversified functionalization of the 4-, 6-, 7-, and 8-positions of 2a with electron-donating groups (EDGs) such as methoxy (2e) and ethoxy (2f) and electronwithdrawing groups (EWGs) such as fluoro (2g, 2k), chloro (2b, 2h), bromo (2c, 2i, 2l), and ester (2d, 2j) is tolerated with good yields. Moreover, methylquinoline-bearing methyl at C 4 also proved to be feasible and afforded the anticipated CF 3tertiary alcohol product 3am in 46% yield. Notably, the established reaction conditions also led to anticipated product 3an when 1-methylisoquinoline (2n) was used as a coupling partner. After examining the tolerance of methylquinoline under the optimized conditions as shown in Table 1, we turned our attention on the various methyl N-heterocycles (2o−q) with 1a. To our delight, various methyl N-heterocycles such as quinoxaline (2o), quinazolinone (2p), and benzothiazole (2q) were reacted with 1a smoothly, which produced various 1-(βcoumarinyl)-1-(β-heterocyclyl)trifluoroethanols in moderate to good yields. Furthermore, 2-methylpyridine (2r) was found to participate in the established reaction, giving 3ar in 44% yield.  To further investigate the scope of this reaction, diversified trifluoromethyl ketones were evaluated (Table 3). Overall, a series of trifluoroacetylcoumarins or trifluoroacetylbenzene equipped with EDGs and EWGs are well tolerated, affording the anticipated trifluoromethyl tertiary alcohols 3ba−ma in 52−95% yields. Specifically, C 6 sites with methyl (1b)-, fluoro (1c)-, chloro (1d)-, and bromo (1e)-modified CF 3 -coumarin ketones reacted smoothly with 2a, delivering desired products with moderate to excellent yields (67−95%). Particularly, a sensitive but versatile iodine group (1f) was also well compatible, which is often used in transition metal-catalyzed cross coupling transformations. Next, C 7 and C 8 sites with strong EDGs such as methoxy (1g, 1h) and ethoxy (1i) are well tolerated, giving rise to anticipated 3ga−ia in 83−88% yields. Notably, disubstituted substrates (1j) and (1k) were well compatible and delivered the corresponding adduct products in 84 and 89% yields, respectively. Meanwhile, the structure of 3ja was also determined by analogy on the basis of X-ray (CCDC 2179504). Gratifyingly, the fused-ring system 1l also reacted smoothly, generating tertiary alcohol product 3la in 89% yield. Finally, it should be mentioned that trifluoroacetophenone (1m) could be subjected as the electrophilic reagent to produce 3ma with moderate yield (52%) in an established metal-free system, which is quite different from previous reports that often rely on Lewis acid catalysis, such as iron salt, indium salt, and so on. 11,12 To further showcase the potential utility of this newly established method, a larger-scale (3 mmol) experiment was carried out between 1k and 2a (Scheme 3), which delivered the desired product 3ka with comparable yield (1.43 g, 88% yield).
Based on the abovementioned results and previous reports, 11 a plausible reaction pathway for the conversion of trifluoromethyl ketone and azaarene to CF 3 -tertiary alcohols under metal-free conditions is outlined in Scheme 4. Initially, 2-methylquinoline 2a was converted to its enamine species G, and then, the enamide species G underwent nucleophilic addition to β-(trifluoroacetyl)coumarin 1a; further protonation could provide the expected azaarene-equipped CF 3 -tertiary alcohol 3aa.
To evaluate the biological activity of the newly prepared azaarene-equipped CF 3 -tertiary alcohols, preliminary antifungal activity against F. oxysporum, F. graminearum, P. nicotianae, F. moniliforme, and R. solani with target compounds 3aa−ma was performed based on the early reference, 15 and the results are summarized in Figure 1. Overall, most of the desired CF 3tertiary alcohol products 3aa−ma showed fungicidal activities against the abovementioned five fungi. First, the inhibitor rate of the model product 3aa against F. oxysporum was 29.84% at 0.5 mg/mL. The inhibitor rate was improved to 44.32 and 45.11% when compounds 3aq and 3ao were used, respectively. Next, compounds 3aa−ma against F. graminearum, P. nicotianae, F. moniliforme, and R. solani were tested. Gratifyingly, the antifungal activity against R. solani was obviously better compared to other three fungi, with a moderate to good inhibitor rate. Particularly, compound 3al displayed good (91.65%) in vitro fungicidal activity, with the median effective concentration (EC 50 ) value of 0.18 mg/mL.

■ CONCLUSIONS
In conclusion, we have developed a novel reaction for the synthesis of azaarene-equipped CF 3 -tertiary alcohols through addition of azaarenes to CF 3 -ketones under metal-free conditions. The azaarenes, including quinolones, isoquinoline, quinoxaline, quinazolinone, and benzothiazole, were used as coupling partners. The corresponding CF 3 -tertiary alcohol products were obtained in excellent yields (up to 95% yield) with high chemoselectivity (only 1,2-addition). Compared to previous reports, this established reaction features simple reaction conditions (only solvent), high atom-and stepeconomy, and broad substrate scope. Moreover, most of the synthesized compounds displayed promising fungicidal activities, and compound 3al exhibited 91.65% fungicidal activity against R. solani, with an EC 50 value of 0.18 mg/mL. Further studies on the synthesis of novel CF 3 -tertiary alcohol scaffolds with green methods and their fungicidal activities are ongoing in our laboratories. Table 3. Scope of Trifluoromethyl Ketones a a ■ EXPERIMENTAL SECTION General Information. All reactions were carried out under an air atmosphere. All reagents were used as received unless otherwise noted. Analytical thin-layer chromatography was performed with 0.25 mm-coated commercial silica gel plates (TLC Silica Gel 60 F 254 ); the developed chromatogram was visualized using fluorescence. Flash chromatography was performed with silica gel (200−300 mesh). Proton nuclear magnetic resonance ( 1 H NMR) data were acquired at 400 MHz on a Bruker Ascend spectrometer. Chemical shifts are reported in delta (δ) units, in parts per million (ppm) downfield from tetramethylsilane. Splitting patterns are designated as s, singlet; d, doublet; t, triplet; and m, multiplet. Coupling constants J are quoted in Hz. Carbon-13 nuclear magnetic resonance ( 13 C NMR) data were acquired at 100 MHz on a Bruker Ascend 400 spectrometer. Chemical shifts are reported in ppm relative to the center line of a triplet at 77.0 ppm for chloroform-d and the center line of a septet at 44.0 ppm for DMSO-d 6 . Fluorine nuclear magnetic resonance ( 19 F NMR) data were acquired at 376 MHz on a Bruker Ascend 400 spectrometer, and chemical shifts are reported relative to interstandard CFCl 3 at 0.0 ppm. Mass spectra were acquired on a Bruker Daltonics MicroTof-Q II mass spectrometer.