Environmentally Friendly Nafion-Catalyzed Synthesis of Substituted 2-Ethyl-3-Methylquinolines from Aniline and Propionaldehyde under Microwave Irradiation

: Herein, we report a facile synthetic methodology for the preparation of 2,3-dialkylquino-lines from anilines and propionaldehydes. This cyclization involved environmentally friendly Nafion ® NR50 as an acidic catalyst with microwave irradiation as the heating source. A series of substituted 2-ethyl-3-methylquinolines were prepared from various anilines and propionaldehyde derivatives through this protocol with good to excellent yields. Some new chemical structures were confirmed by X-ray single-crystal diffraction analysis and the related data were provided. The plausible reaction mechanism studies are also discussed.

In continuation of our investigations toward the synthesis of nitrogen-containing heterocyclic compounds [68][69][70][71], we recently provided a synthetic route for the Friedländer quinoline synthesis from 2-aminobenzophenone and acetylacetone catalyzed by Nafion ® NR50 particles under microwave irradiation ((1) in Scheme 2) [69]. Nafion ® is a commercially available synthetic polymer particle which possesses ionic properties [72]. Its unique ionic properties result from the copolymerization of incorporating perfluorovinyl ether groups terminated with sulfonate groups onto a tetrafluoroethylene (PTFE) skeleton [73]. The chemical structure of Nafion ® NR50 is shown in Scheme 2. Considering the importance of alkylated quinolines in medicinal chemistry, the efficiency of microwave irradiation and recyclable features of Nafion ® NR50 in green chemistry, the development of a facile synthetic protocol is of great interest. Herein, we provide an efficient synthetic protocol for the preparation of a 2-ethyl-3-methylquinoline skeleton from aniline and propionaldehyde using Nafion ® NR50 with good to excellent yields under microwave irradiation ((2) in Scheme 2). Four chemical structures are confirmed by X-ray single-crystal diffraction analysis. Scheme 2. Nafion ® NR50-mediated synthesis of quinolines.

Results and Discussions
Initially, we conducted the investigation with the cyclization of readily available aniline 1a and propionaldehyde 2a as model substrates in the solvent under microwave irradiation (T = 150 °C), and the related results are summarized in Table 1. By using liquid acids, such as AcOH (acetic acid), TFA (trifluoroacetic acid), and TfOH (triflic acid), quinoline 1a was obtained at 15% to 40% yield (entries 1-3). The involvement of substituted sulfonic acids, including MsOH (methansulfonic acid), BsOH (benzenesulfonic acid), and p-TsOH.H2O (p-toluenesulfonic acid) provided product 3a in similar yields (entries [4][5][6]. Other metal triflates such as AgOTf, Bi(OTf)3, Fe(OTf)2, Fe(OTf)3, and Sn(OTf)2 were also examined in this reaction, as shown in entries 7-11, and the isolated yields of 3a were lower than that obtained after using sulfonic acids. Other Lewis acids including BF3.OEt2, InCl3, and AlCl3 promoted the reactions, and the isolated yields are shown in entries 12-14. Among these entries, BF3.OEt2 showed the best performance. According to our previous work [69], we further examined the environmentally friendly solid acid Nafion ® NR50, and the desired product 3a was obtained at 93% yield (entry 15). However, only a 30% yield of 3a was observed when liquid Nafion ® NR117 was used as an acid catalyst (entry 16). No better yields were observed by changing the reaction solvents (entries [17][18][19][20]. Changing the heating source from microwave irradiation to normal hot plate, the yield was decreased to 40% yield. It is possible that the boiling point of propionaldehyde is lower than the reaction temperature, and the reaction was conducted in the open system (entry 21). Considering the green chemistry concept and environmentally friendly nature, we selected Nafion ® NR50 as acid and ethanol as a solvent under microwave irradiation as the best reaction condition for this synthetic protocol. Microwave irradiation has attracted considerable attention in the past decade for increasing reaction efficiency [74,75]. Therefore, we confirmed that the condition of entry 15 is the most suitable condition in this double intermolecular cyclization for the construction of the corresponding 2-ethyl-3-methylquinolines.
After obtaining the optimal reaction conditions, the scope of the reaction with respect to various anilines was evaluated. As shown in Scheme 3, a variety of commercially available anilines, 1b-1p, were investigated with propionaldehyde 2a in this intermolecular reaction. The anilines containing both electron-withdrawing groups (EWGs) and electrondonating groups (EDGs) on different positions successfully gave good to excellent yields of the corresponding quinolines 3b-3p. The structure of 3p was confirmed by single-crystal X-ray crystallography [76]. Quinolinyl ketones are regarded as a versatile directing group by the cooperation of transition metal catalysts for activating the organic transformation [77][78][79][80][81][82]. A variety of 2aminobenzophenone 4 were subjected to react with propionaldehyde 2a in the optimized reaction condition. As shown in Scheme 4, a wide range of 2-aminobenzophenones could be used in this cyclization. Various substituted groups at different positions of the Ar 1 and Ar 2 rings smoothly delivered good to excellent yields of the desired 8-substituted quinolinyl ketones 5 in 2 h. Not only non-substituted 2-aminobenzophenone 4a, but some functional groups such as chloro-(4b), bromo-(4c), methyl-(4d), dimethoxy-(4e), phenyl-(4f), p-methoxyphenyl-(4g) and p-fluorophenyl-(4h) on the Ar 1 ring; fluoro-(4i), chloro-(4j), bromo-(4k), methyl-(4l), methoxy-(4m), trimethoxy-(4n) on Ar 2 , and both EWGs dichloro-(4o) and both EWGs multimethoxy-(4p-4s) on the Ar 1 and Ar 2 rings were well tolerated in this transformation. The related 8-substituted quinolinyl ketones 5 are illustrated in Scheme 4. The structures of 5a, 5b, and 5d were also confirmed by single-crystal X-ray crystallography [76]. We next investigated the scope of substituents on the terminal of propionaldehyde by using aniline 1a and 2-aminobenzophenone 4a as the model aminobenzene substrate. Four propionaldehyde analogues were investigated, including valeraldehyde 2b, isovaleraldehyde 2c, 3-phenylpropionaldehyde 2d and 4,4,4-trifluorobutyraldehyde 2e. As illustrated in Scheme 5, changing the substituted group on propionaldehydes 2 did not influence the preparation of corresponding quinolines 6a-6h and gave modest to good yields. Based on our previous experience for the synthesis of quinolines by Friedländer reaction from 2-aminobenzophenone 4a with monocarbonyl synthons [69], it is possible that the electron-withdrawing CF3 group on 2e change in α-methylene reactivity could also access the Friedländer-type protocol to prepare the desired quinoline 7 by decreasing to one equivalent (Scheme 6). Friedländer quinoline synthesis is the reaction of 2-aminobenzaldehyde with acetylaldehyde to generate quinoline skeleton. In 2020, we developed a Nafion ® NR50-catalyzed Friedländer quinoline synthesis; the related mechanism was also reported [69].  To observe the efficiency of the environmentally friendly Nafion ® NR50 particles, the recycling experiments were conducted at least 10 times, and the corresponding yields are shown in Figure 1. Photos of the physical states for every experiment are provided in Table S1 in the Supporting Information. The recovered Nafion ® NR50 particles was reused 10 times in the reaction of 1a and 2a. Although the shapes of particles became different, no obvious yield change was observed. On the basis of the abovementioned results, four new chemical structures are confirmed by single-crystal X-ray crystallography. The corresponding crystal structures of 3p, 5a, 5b and 5d, and related data are described in Table 2. Furthermore, no alert A and B are presented in the checkcif output, as reported in the Supplementary Materials file.

General Information
All reagents and solvents were commercially available (Sigma-Aldrich, St. Louis, MO, USA) and used without further purification. Reactions were routinely performed using the Discover SP system (2010 version, CEM Corporation, Matthews, NC, USA) in the sealed reaction vessels in standard mode with the temperature monitored using a vertically focused IR sensor. All reactions were monitored by TLC on silica gel 60 F254 (Merck) with detection by UV light. Column chromatography was performed using silica gel (200-300 mesh). Products in organic solvents were dried with anhydrous magnesium sulfate before concentration in vacuo. Melting points were determined with a MP-2D (Mandarin In Scientific, New Taipei, Taiwan) melting apparatus. 1 H and 13 C NMR spectra were recorded on a Bruker AVIII 500 MHz instruments operating at 500 and at 125 MHz, respectively. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, br = broad), coupling constants (Hz) and integration. HRMS were obtained on a Waters LCT Premier XE (Waters Corp., Manchester, UK) instrument equipped with an electrospray source. The X-ray intensity data were measured at low temperature 100 K using Mo Kα radiation diffractometer equipped with a kappa geometry goniometer and corrected for absorption effects using the numerical method (SA-DABS). The yields are provided in mol% and the corresponding product weights are also shown.

Conclusions
In summary, an environmentally friendly and atom-economical synthetic route is reported for the preparation of functionalized 2,3-dialkylquinolines from substituted anilines and functionalized propionaldehydes using Nafion ® NR50 as an acidic catalyst. The reaction worked well with various substituted anilines and propionaldehydes and provided the corresponding quinolines in good to excellent yields. A series of quinolinyl ketones were also synthesized, indicating that this reaction features good functional group tolerance. Moreover, the Nafion ® NR50 particles could be repeatedly used and exhibit good efficiency, demonstrating their environmentally friendly properties. Four structures were confirmed by single-crystal X-ray crystallography. Further investigations of Nafion ® NR50 particles are currently underway in our group.
Supplementary Materials: The following are available online at www.mdpi.com/article/10.3390/catal11080877/s1. Detailed experimental procedures and spectroscopic data for all compounds and X-ray analysis data for 3p, 5a, 5b and 5d (PDF).