Associate Editor: P. J. Skabara
Beilstein J. Org. Chem. 2021, 17, 2799–2811. https://doi.org/10.3762/bjoc.17.191
Received 20 Aug 2021, Accepted 19 Nov 2021, Published 01 Dec 2021
A non-peer-reviewed version of this article has been posted as a preprint https://doi.org/10.3762/bxiv.2021.60.v1
A new series of ten examples of Schiff bases, namely (E)-2-(((2-alkyl(aryl/heteroaryl)-4-(trifluoromethyl)quinolin-6-yl)imino)methyl)phenols 3, was easily synthesized with yields of up to 91% from the reactions involving a series of 2-(R-substituted) 6-amino-4-(trifluoromethyl)quinolines 1 and 4(5)-R1-substituted salicylaldehydes 2 – in which alkyl/aryl/heteroaryl for 2-R-substituents are Me, Ph, 4-MeC6H4, 4-FC6H4, 4-NO2C6H4, and 2-furyl, and R1-substituents are 5-NEt2, 5-OCH3, 4-Br, and 4-NO2. Complementarily, the Schiff bases showed low to good quantum fluorescence yield values in CHCl3 (Φf = 0.12–0.80), DMSO (Φf = 0.20–0.75) and MeOH (Φf = 0.13–0.85). Higher values of Stokes shifts (SS) were observed in more polar solvents (DMSO; 65–150 nm and MeOH; 65–130 nm) than in CHCl3 (59–85 nm). Compounds 3 presented good stability under white-LED irradiation conditions and moderate ROS generation properties were observed.
Keywords: photophysical properties; photostability; quinoline; ROS generation; Schiff base
Schiff bases are an important class of organic compounds first reported by the German chemist Hugo Schiff in 1864 and are formed from the reversible condensation between a primary amine and an aldehyde or a ketone . Also known as azomethines, aldimines, and more commonly as imines, Schiff bases have the general organic function -C=N- , and are known to have a wide range of biological activities, including antioxidant , antitubercular , antibacterial , antimicrobial , and antifungal properties , in addition to their role as chemosensors  (Figure 1).
Quinolines are another important class of compounds and have numerous medicinal chemistry applications due to their biological applicability  and promising antimycobacterial , antimalarial [11,12], and antibacterial  activities. On the other hand, 6-aminoquinoline compounds demonstrate interesting luminescent properties  that have attracted great interest because of their potential applicability in the composition of organic light-emitting diodes (OLED), organic solar cells (OSC), and biomolecular markers [15,16].
Moreover, the trifluoromethyl substituent (CF3) is an interesting electron-withdrawing group that enhances the effects of many bioactive molecules due to a significant improvement in stability, lipophilicity, and resistance to enzymatic degradation [17,18]. Also, it has been widely applied as a special alkyl substituent for ligands of phosphorescent heavy metal complexes in OLEDs. Due to the ability to increase the electron transport and decrease molecule stacking, trifluoromethyl-substituted molecules have been employed to the development of phosphorescent materials [19-21].
On the other hand, antioxidants are known for protecting organisms against cell damage caused by oxidative stress, especially by eliminating reactive oxygen species (ROS) such as hydroxyl radicals (•OH), superoxide anions (O2•‒), and singlet oxygen (1O2) [3,22,23]. Therefore, research in recent years has focused on new compounds obtained from natural sources or by synthetic methods, which provide active ingredients to prevent or reduce the effects of oxidative stress in cells.
Recently, our research group reported the synthesis of 6-amino-4-(trifluoromethyl)quinolines, which were obtained through an electrophilic aromatic substitution reaction catalyzed by sulfuric acid from 4-substituted 4-methoxy-1,1,1-trifluoroalk-3-en-2-ones in a two-step reaction procedure and with satisfactory yields of up to 87%. The prepared 6-aminoquinolines presented promising photophysical properties and high thermal stability .
In this sense, the present study aimed to synthesize a novel trifluoromethylated hybrid system comprising the Schiff base scaffolds from some 6-aminoquinolines and salicylaldehyde derivatives in order to analyze and evaluate their photophysical, photostability, and antioxidant properties for possible future applications in the pharmacological areas or materials sciences (Scheme 1).
First, a series of six 6-amino-2-alkyl(aryl/heteroaryl)-4-(trifluoromethyl)quinolines 1a–f was synthesized via an intramolecular cyclization reaction, in which trifluoromethyl-substituted enamino ketones reacted with concentrated sulfuric acid at adequate temperature (120 °C) and time (10 hours) to furnish the desired compounds, following the method already described in the literature by our research group .
With the quinolines 1a–f at hands we initially selected quinoline 1b and salicylaldehyde (2a) to optimize the reaction conditions leading to Schiff bases 3.
Hence, the reaction solvent and molar ratio between the precursors were evaluated. The reactions were carried out using an equimolar ratio of both reactants in methanol, ethanol, and acetonitrile as solvent at reflux temperature according to previously reported data [22,24,25]. Thus, we found increasing yields for 3ba depending on the solvent used, i.e., 70% (methanol), 80% (ethanol), and 83% (acetonitrile).
Based on these results, we selected acetonitrile as the best solvent for further optimization. When changing the molar ratio of the reactants to a 1:2 molar ratio of quinoline 1b and salicylaldehyde (2a), the yield of the desired product 3ba increased to 90%. The best result was obtained when quinoline 1b (1 mmol) was added to the salicylaldehyde (2a, 2 mmol) in acetonitrile (10 mL) and refluxing the mixture for 48 h. Under these conditions, the reactions of quinolines 1a–f with salicylaldehyde (2a) afforded the desired Schiff bases 3aa–fa (6 examples) with 20–90% yields for the isolated products after recrystallization from ethanol (Scheme 2).
In order to evaluate the properties related to the substituents of the portion provided by salicylaldehyde, the same optimized conditions were applied to the reaction of quinoline 1b (R = C6H5) with various salicylaldehydes 2b–e, resulting in four more Schiff bases 3bb–be with 40–89% yield for the isolated products after recrystallization from ethanol (Scheme 3).
With some exceptions, electron-deficient or electron-rich substituted 2-aryl-6-aminoquinolines and aromatic aldehydes worked very well to furnish the Schiff bases 3. However, a poor yield (20%) was observed when 2-methyl-6-aminoquinoline (1a) was employed to obtain the derivative 3aa. We initially speculated that a competition between the 6-amino group and the 2-methyl substituent present in quinoline 1a might have occurred, as described by Fu and co-workers , which could lead to only the respective 2-alkenylquinoline or to simultaneous reaction products from both moieties (6-amino and 2-methyl substituents). However, at the end of the reaction only the Schiff base 3aa could be isolated and the 2-alkenylquinoline derivative was not identified by GC or 1H NMR.
In contrast to the yield obtained for the synthesis of 3bc (R1 = 5-OMe, 75%), the aromatic aldehyde 2c substituted with a similar electron-rich group (R1 = 5-NEt2) gave only a regular 40% yield for 3bb.
The structures of the new Schiff bases 3 were characterized by 1H, 13C, and 19F NMR spectroscopy and HRMS techniques. The structural assignments for the synthesized quinolines 1a–f were consistent with the 1H, 13C, and 19F NMR spectra described in the literature . When the 1H NMR spectral data were recorded in CDCl3 as a solvent for the 3aa–be series and compared with the NMR spectral data of the 1a–f series, the lack of the chemical shift related to the signal for the NH2 group was clearly noted, which was always present in the series of quinolines 1 at 4.51 ppm, on average. The appearance of a singlet for the azomethine proton (CH=N) with a chemical shift in the 8.53–8.77 ppm region in all 1H NMR spectra supported the structures of the Schiff bases 3. Additionally, the hydrogens of the hydroxy group were observed at 13.12 ppm, on average.
The analysis of the 13C NMR spectra in CDCl3 for the new Schiff bases 3 showed chemical shifts in the 162.68–164.71 ppm range for the CH=N moiety, which agrees with similar structures described in the literature [7,14,22]. The CF3 group bonded at C-4 was assigned as a quartet with 1JCF ≈ 274.6 Hz, with chemical shifts of 123.52 ppm, on average. The 19F NMR spectra in CDCl3 showed a singlet at −61.70 ppm, on average, in relation to the CF3 group. Furthermore, there were no significant differences in the chemical shift values between the quinoline precursor and new Schiff bases regarding the aromatic resonances in the 1H NMR and 13C NMR data.
Studies in the literature have reported that the imine group may exist as E/Z geometrical isomers in the –CH=N double bond . Moreover, the E geometrical isomer in the –CH=N- double bond has a higher percentage when in dimethyl sulfoxide-d6 solution. On the other hand, the Z isomer can be stabilized in less polar solvents by an intramolecular hydrogen bond. In the present study, the spectral data were recorded in CDCl3 solution and no signal belonging to the Z isomer was observed in all cases, which can be confirmed by the chemical shift values in the 1H NMR regarding the –CH=N bond.
Finally, in order to determine the real molecular structure of the Schiff bases 3, single-crystal X-ray diffraction (SC-XRD) was performed for compound 3ba in the solid state (Figure 2). The compound crystallized in the P21/c space group, and it was possible to verify that the dihedral angles between the substituent (C6H5) and quinoline ring (N1–C2–C21–C26) were 18.1°. The dihedral angles between the quinoline ring and the substituent (C6H4) C(621)–C(62)–N(61)–C(6) were 179.0°, which shows some degree of planarity over the entire molecule. Additional bond lengths and angles and crystallographic refinement details can be found in the Supporting Information File 1 (Tables S1and S2).
The photophysical study for the series of compounds 3aa–fa and 3bb–be was carried out using chloroform (CHCl3), methanol (MeOH) or dimethyl sulfoxide (DMSO) solutions. As comparison, the UV–vis absorption spectra of compounds 3ea and 3be, which contain the nitro group in two different ring positions of the molecules recorded in the three solvents are depicted in Figure 3. The values of maximum molar absorption coefficients (in log ε) and wavelengths (nm) of all compounds are listed in Table 1.
Table 1: Photophysical data of derivatives 3aa–fa and 3bb–be ([ ] = 1.50 × 10−5 M).
|Compound (CHCl3)||λ, nm (log ε)||Emission nm (Φf)a||SS (nm/cm−1)b||E0-0 (in eV)c|
|3aa||275 (4.76), 354 (4.64)||451 (0.90)||97/6075||3.10|
|3ba||274 (4.71), 369 (4.65)||442, 546 (0.71)||73/4475||2.95|
|3ca||276 (4.64), 370 (4.59)||430, 547 (0.70)||60/3770||3.10|
|3da||274 (4.69), 368 (4.64)||438, 544 (0.74)||70/4340||3.00|
|3ea||289 (4.61), 373 (4.67)||439, 556 (0.16)||66/4030||2.90|
|3fa||280 (4.72), 383 (4.71)||451 (0.69)||68/3935||2.90|
|3bb||274 (4.31), 322 (4.26), 420 (4.78)||457 (0.92)||37/1925||2.60|
|3bc||267 (4.53), 293 (4.40), 375 (4.70)||440, 526 (0.65)||65/3940||3.05|
|3bd||273 (4.71), 371 (4.61)||557 (0.81)||186/9000||2.95|
|3be||271 (4.78), 366 (4.68)||438, 524 (0.66)||72/4490||3.00|
|Compound (DMSO)||λ, nm (log ε)||Emission nm (Φf)a||SS (nm/cm−1)b||E0-0 (in eV)c|
|3aa||277 (4.50), 354 (4.58)||481 (0.96)||127/7460||2.80|
|3ba||276 (4.73), 371 (4.66)||490 (0.94)||119/6545||2.75|
|3ca||278 (4.52), 374 (4.46)||488 (0.95)||114/6245||2.75|
|3da||276 (4.48), 372 (4.42)||491 (0.96)||119/6515||2.75|
|3ea||294 (4.22), 380 (4.42)||488 (0.93)||108/5825||2.75|
|3fa||281 (4.46), 386 (4.55)||491 (0.85)||105/5540||2.70|
|3bb||273 (4.37), 326 (4.15), 431 (4.64)||573 (0.95)||142/5750||2.45|
|3bc||275 (4.34), 296 (4.41), 381 (4.72)||491 (0.96)||110/5880||2.80|
|3bd||275 (4.32), 374 (4.24)||489 (0.89)||115/6290||2.75|
|3be||282 (4.73), 336 (4.39), 376 (4.51), 423 (4.27)||489 (0.80)||66/3190||2.75|
|Compound (MeOH)||λ, nm (log ε)||Emission nm (Φf)a||SS (nm/cm−1)b||E0-0 (in eV)c|
|3aa||273 (4.35), 356 (4.23)||484 (0.86)||128/7430||2.70|
|3ba||273 (4.27), 372 (4.37)||489 (0.85)||117/6430||2.90|
|3ca||273 (4.65), 367 (4.58)||486 (0.85)||119/6670||2.80|
|3da||275 (4.61), 331 (4.43), 369 (4.39)||490 (0.83)||121/6690||2.80|
|3ea||280 (4.30), 371 (4.28)||485 (0.40)||114/6335||2.90|
|3fa||276 (4.55), 382 (4.54)||488 (0.75)||106/5685||2.77|
|3bb||273 (4.19), 345 (4.63), 427 (4.06)||490 (0.91)||63/3010||2.80|
|3bc||272 (4.25), 371 (4.36)||499 (0.94)||128/6915||2.80|
|3bd||274 (4.43), 371 (4.25)||483 (0.84)||112/6250||2.80|
|3be||275 (4.51), 325 (4.48), 370 (4.32)||490 (0.82)||120/6620||2.75|
aUsing 9,10-diphenylanthracene (DPA) as standard in CHCl3 (Φf = 0.65; λexc = 366 nm); bSS = Stokes shifts: Δλ = 1/λabs − 1/λem; cdetermined from the interception of the normalized absorption and fluorescence emission spectra; E0-0 = 1240/λ (eV).
The absorption spectra of the studied Schiff base series presented electronic transitions in the 250–500 nm UV–vis region. In the ultraviolet range, the observed transitions can be attributed to the π → π* transitions and refer to the heterocyclic ring. Transitions above 350 nm can be attributed to the n → π* transition referring to the imine moiety, causing an intramolecular charge-transfer type (ICT) transition . Complementary, according to Temel and co-workers who studied a similar scaffold, namely, 4-bromo-2-((quinoline-8-yl)methyl)phenol , no imine–hemiaminal tautomer peak transition was observed for the Schiff bases 3.
In general, there were slightly significant changes in the transitions according to the changes in the substituent or polarity of the solvent (behavior in CHCl3, MeOH, and DMSO is quite similar). Notably, one can highlight compound 3bb (R = Ph, R1 = 5-NEt2) which transitions vary significantly with the change in polarity of the medium (4–24 nm), and this may be due to the donor diethylamino group attached to the imine portion of the molecule. In comparison to the absorption spectra of aminoquinolines published by Kappenberg and co-workers , the Schiff bases studied here show similar absorption behavior, making it clear that these transitions originate mainly from the substituents (NH2, CF3, and R) attached to the quinoline heterocycle ring, respectively.
Moreover, as shown in Figure 3, the position of the substituent in the molecule (as exemplarily shown for compounds 3ea and 3be) in the same solvent and in solvents of different polarities affect the values of the wavelengths and molar absorption coefficients of the derivatives studied here. All absorption spectra are listed in Supporting Information File 1 (Figures S2–S7).
The steady-state fluorescence emission spectra of the Schiff base compounds from their absorption in the UV–vis region was carried out. Derivatives 3aa–fa and 3bb–be were analyzed in CHCl3, DMSO, and MeOH solutions by the emission and excitation spectra and exemplified in the Supporting Information File 1 (Figures S2–S7). For emission measurements, the maximum wavelength with the lowest absorption energy was used for excitation for the fluorescence measurements. The quantum fluorescence yields (Φf) were calculated in order to prove the quantum efficiency of these derivatives in terms of fluorescence emission and thus discuss the influence of the different solvents and substituents. Firstly, by comparing the selected solvents, compound 3aa (R = Ph, R1 = H) presented an emission in the 400–550 nm region depending on the solvent polarity (CHCl3, DMSO, and MeOH). Therefore, it is possible to infer that the polarity of the solvents directly influences the electronic transitions in the excited state, with significant changes for the compound in more polar and protic solvents, by shifting the emission maxima to lower energy values (Figure 4).
Another possible comparison is between substituents with electron-donating and accepting properties in the same solvent media. Therefore, when the compounds containing a diethylamino group (3bb, R = Ph, R1 = 5-NEt2) and a nitro group (3be, R = Ph, R1 = 4-NO2) were analyzed, a significant difference was observed compared to the other compounds in the series 3. Thus, we can say that these characteristics exist because there is more stabilization of the excited state in a polar environment (DMSO and MeOH), adding to a possible push–pull effect of the diethylamino group (donor group) [14,28,29]. Moreover, these results should indicate a negative possibility of excited state intramolecular proton transfer (ESIPT) phenomena occurring (in protic MeOH solvent and low values of Stokes shifts), being only a direct influence of the substituents on the excited state (Figure 5 and Table 1) [30,31].
In general, the Schiff bases showed variable quantum fluorescence yields in CHCl3, DMSO and MeOH solutions (see Table 1), using 9,10-diphenylanthracene (DPA) as standard molecule by comparative method. An analysis of the obtained Φf values revealed significant differences, mainly according to the change in solvent polarity, being, for example, higher for compounds in DMSO and MeOH than in chloroform solution. Furthermore, the highest values were found in the presence of electron-donating groups, i.e., in compounds 3bb (R = Ph, R1 = 5-NEt2) and 3bc (R = Ph, R1 = 5-OMe) (Table 1). These values observed according to the solvent may be related to the stabilization of the excited state in each solution.
Regarding the Stokes shifts (SS), higher values were observed for derivatives in a more polar solvent (DMSO and MeOH) than in CHCl3 (Table 1) and also depending on the electronic properties of the substituents in the molecules. According to the characteristics and properties described herein, once again, we can attribute these differences to the stabilization of the excited states in more polar solvents combined with the properties of electron-donating groups (push–pull system).
As in the aminoquinolines described in the literature , the Schiff base derivatives present emission spectra in a different region to the amino derivatives (blue to green region), but with higher quantum fluorescence yields and Stokes shifts, a fact attributed to a greater electronic conjugation provided by the imine function present in the molecules of the series 3.
In order to be efficient for applications in photobiology, organic dyes must be stable when subjected to light irradiation for long periods of time. Thus, the photostability parameter is an important characteristic considering that photogenerated singlet oxygen (1O2) can react with a dye molecule, promoting its degradation . Based on the changes in the UV–vis absorption spectra as a function of time, the Schiff base derivatives 3aa–fa and 3bb–be were confirmed to present good photostability under white-light LED irradiation conditions (25 mW/cm2 fluence rate and 90 J/cm2 light dosage) in the 400–800 nm range for 60 min in DMSO solution (Figure 6).
The ability of the Schiff bases 3aa–fa and 3bb–be to produce 1O2 species was studied in DMSO solution using a 1,3-diphenylisobenzofuran (DPBF) photooxidation assay and the adequate equation as described by Pivetta and co-workers . In this study, the methylene blue dye (MB) was used as a reference. The photooxidation rate constants (k) and 1O2 yield of derivatives (ΦΔ) were determined and the values are presented in Table 2. All UV–vis spectra of the DPBF photooxidation are shown in Supporting Information File 1 (Figures S8–S17).
Table 2: Photooxidation rate constants and singlet oxygen quantum yield of compounds 3aa–fa and 3bb–be in DMSO solution.
|Compound||R||R1||k (min−1)||ΦΔ||Compound||R||R1||k (min−1)||ΦΔ|
|3aa||Me||H||2.6 × 10−4||0.19||3bb||Ph||5-NEt2||7.0 × 10−4||0.51|
|3ba||Ph||H||2.2 × 10−4||0.16||3bc||Ph||5-OMe||2.5 × 10−4||0.18|
|3ca||4-MeC6H4||H||1.0 × 10−4||0.07||3bd||Ph||4-Br||1.6 × 10−4||0.12|
|3da||4-FC6H4||H||5.4 × 10−4||0.40||3be||Ph||4-NO2||1.3 × 10−4||0.09|
|3ea||4-NO2C6H4||H||1.9 × 10−4||0.14||MBa||–||–||7.7 × 10−4||0.52|
|3fa||2-Furyl||H||2.3 × 10−4||0.17||RhBb||–||–||6.3 × 10−4||0.78|
In general, all compounds at a concentration of 0.5 μM showed weak photooxidization tendency against DPBF quencher at 50 μM (e.g., 3bb; Figure 7). In this way, Schiff bases presented moderate singlet oxygen species generator character (ΦΔ between 0.07–0.51) after 600 s of irradiation with a red-light diode laser source (λ = 660 nm, 100 mW).
The moderate generation of singlet oxygen species may be attributed to the formation of other possible reactive oxygen species in DMSO solution (e.g., hydroxyl and superoxide radical species) that are not identified by the type of photooxidation assay employed in this work. The good photostability and tendency of these Schiff base derivatives to generate 1O2 under light irradiation demonstrated here highlights their potential as dyes in photobiological applications.
In conclusion, we reported the synthesis and photophysical and antioxidant properties of a new series of ten novel Schiff bases 3. The scaffolds 3 could be synthesized by a simple condensation reaction between 6-aminoquinolines and salicylaldehydes and an easy purification methodology with yields of up to 91%. Photophysical experiments with the derivatives exhibited common transitions in these heterocycle units and corroborated the aromatic structures and good fluorescence quantum yield values for all compounds. Additionally, good photostability and moderate ROS generation may be interesting features for applying these derivatives in photooxidation and photodamage reactions to biomolecules.
Unless otherwise indicated, all reagents and solvents were used as obtained from commercial suppliers and without further purification. 1H and 13C NMR spectra were acquired on a Bruker DPX 400 MHz spectrometer for one-dimensional experiments and on a Bruker Avance III 600 MHz for 19F NMR spectra and 2D-experiments (gHMBC). NMR spectra were recorded using 5 mm sample tubes, at 298 K, at a digital resolution of ±0.01 ppm in CDCl3 with TMS as the internal reference. All results are reported as follows: Chemical shift (δ) (multiplicity, coupling constant, integration). The following abbreviations were used to explain multiplicities: s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, qui = quintet, m = multiplet, dd = doublet of doublets. All NMR chemical shifts are reported in parts per million relative to the internal reference. All melting points were determined using coverslips on a Microquímica MQAPF-302 apparatus. FTIR spectra were recorded using the ATR sampling mode on a Bruker VERTEX 70 spectrophotometer with Platinum ATR accessory (diamond crystal) in the 4000–400 cm−1 region. High-resolution mass spectra (HRMS) were obtained for all compounds on a hybrid high-resolution and high-accuracy (5 μL/L) micro Q-TOF mass spectrometer (Bruker Scientific®, Billerica, MA, USA) at the Caxias do Sul University – UCS, Brazil. The found HRMS values were within 0.003 m/z unit of the calculated values, as following: 3aa (0.001 m/z), 3ba (0.002 m/z), 3ca (0.0001 m/z), 3da (0.0004 m/z), 3ea (0.0001 m/z), 3fa (0.0005 m/z), 3bb (0.003 m/z), 3bc (0.003 m/z), 3bd (0.0000 m/z) and 3be (0.0003 m/z). CHN elemental analyses were performed using a Perkin Elmer CHNS/O Analyzer 2400 Series II at the Federal University of Rio Grande do Sul – UFRGS and the values obtained for carbon, hydrogen, and nitrogen agreed with the calculated values within 0.5%. All NMR and FTIR spectra can be found in Supporting Information File 1 (Figures S38–S47). Single crystals of compound 3ba were obtained by slow evaporation of a CDCl3 solution at 25 °C. Diffraction measurement of compound 3ba was performed using a Bruker D8 QUEST diffractometer using Cu Kα radiation (λ = 1.54178 Å) with a KAPPA four-circle goniometer equipped with a PHOTON II CPAD area detector, at a temperature of 296 K. For spectroscopic analysis, UV–vis absorption spectra were recorded using a Shimadzu UV2600 spectrophotometer (2.0 nm data range), using DMSO, MeOH or chloroform as solvent. The steady-state emission fluorescence spectra in DMSO, MeOH or chloroform solutions were measured with a Cary50 Eclipse Fluorescence Spectrophotometer (excitation/emission; slit 2.5 mm). All spectra can be found in Supporting Information File 1 (Figures S2–S7). Photostability assays were performed using white-light LED array system irradiation (visible range) at 25 mW/cm2 and total light dosage 90 J/cm2 at 60 min, according to the current literature. All experiments were performed in duplicate and independently. In order to measure 1O2 generation ability, UV–vis spectra of the solutions (samples and standard) were recorded for different exposure times by using a 660 nm red light diode laser positioned 2.0 cm from the sample (TheraLase DMC, São Carlos, SP, Brazil) with an average power of 100 mW, during 10 min (irradiation intervals every 30 s). All spectra are provided in Supporting Information File 1 (Figures S8–S17).
A mixture of the respective 6-amino-2-alkyl(aryl/heteroaryl)-4-(trifluoromethyl)quinoline (1a–f, 1.0 mmol) and salicylaldehyde (2a–e, 2.0 mmol) in anhydrous acetonitrile (10.0 mL) was heated for 48 h at reflux temperature. After completion of the reaction (TLC) and cooling the mixture to room temperature, the solid was filtered under reduced pressure. The crude compounds 3 were purified by recrystallization from ethanol to provide the desired (E)-2-(((4-(trifluoromethyl)quinolin-6-yl)imino)methyl) phenols 3 in 20–91% yield.
(E)-2-(((2-Methyl-4-(trifluoromethyl)quinolin-6-yl)imino)methyl)phenol (3aa): Yellow solid, yield 20%; mp 129–132 °C; 1H NMR (400 MHz, CDCl3) δ 12.98 (s, 1H, OH), 8.72 (s, 1H, CH=N), 8.15 (d, J = 8.9 Hz, 1H, H-8), 7.85 (bs, J = 2.1 Hz, 1H, H-5), 7.74 (dd, J = 9.0, 2.3 Hz, 1H, H-7), 7.61 (s, 1H, H-3), 7.48–7.39 (m, 2H, C6H4OH), 7.09–7.03 (m, 1H, C6H4OH), 6.98 (td, J = 7.5, 1.1 Hz, 1H, C6H4OH), 2.82 (s, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3) δ 164.11 (CH=N), 161.18 (C6H4OH), 158.14 (C-2), 147.63 (C-8a), 147.20 (C-6), 134.40 (q, J = 31.6 Hz, C-4), 133.76 (C6H4OH), 132.67 (C6H4OH), 130.94 (C-8), 124.85 (C-7), 123.36 (q, J = 274.0 Hz, CF3), 121.85 (C-4a), 119.64 (q, J = 5.3 Hz, C-3), 119.29 (C6H4OH), 119.01 (C6H4OH), 117.37 (C6H4OH), 114.75 (t, J = 2.2 Hz, C-5), 25.34 (CH3) ppm; 19F NMR (565 MHz, CDCl3) δ −61,71 (CF3) ppm; FTIR (ATR) ν: 3061 (ν OH), 1627 (ν CH=N), 1118 (ν C-O) cm−1; HRMS–ESI (m/z): [M + H]+ calcd for C18H14F3N2O, 331.1053; found, 331.1037.
(E)-2-(((2-Phenyl-4-(trifluoromethyl)quinolin-6-yl)imino)methyl)phenol (3ba): Yellow solid, yield 90%; mp 183–186 °C; 1H NMR (600 MHz, CDCl3) δ 12.96 (s, 1H, OH), 8.71 (s, 1H, CH=N), 8.27 (d, J = 8.9 Hz, 1H, H-8), 8.20–8.14 (m, 3H, Ph, H-3), 7.87 (bs, 1H, H-5), 7.74 (dd, J = 8.8, 2.3 Hz, 1H, H-7), 7.54 (t, J = 7.3 Hz, 2H, Ph), 7.49 (t, J = 7.1 Hz, 1H, Ph), 7.45–7.38 (m, 2H, C6H4OH), 7.05 (d, J = 8.2 Hz, 1H, C6H4OH), 6.96 (t, J = 7.4 Hz, 1H, C6H4OH) ppm; 13C NMR (151 MHz, CDCl3) δ 164.09 (CH=N), 161.23 (C6H4OH), 156.13 (C-2), 148.02 (C-8a), 147.58 (C-6), 138.09 (Ph), 134.80 (q, J = 31.6 Hz, C-4), 133.81 (C6H4OH), 132.71 (C6H4OH), 131.96 (C-8), 130.11 (Ph), 129.03 (Ph), 127.36 (Ph), 125.08 (C-7), 123.50 (q, J = 274.9 Hz, CF3), 122.44 (C-C4a), 119.29 (C6H4OH), 119.01 (C6H4OH), 117.38 (C6H4OH), 116.48 (q, J = 5.1 Hz, C-3), 114.71 (C-5) ppm; 19F NMR (565 MHz, CDCl3) δ −61.62 (CF3); FTIR (ATR) ν: 3057 (ν OH), 1625 (ν CH=N), 1029 (ν C-O) cm−1; HRMS–ESI (m/z): [M + Na]+ calcd for C23H15F3N2NaO, 415.1029; found, 415.1007.
(E)-2-(((2-(p-Tolyl)-4-(trifluoromethyl)quinolin-6-yl)imino)methyl)phenol (3ca): Yellow solid, yield 81%; mp 210–213 °C; 1H NMR (600 MHz, CDCl3) δ 12.98 (s, 1H, OH), 8.72 (s, 1H, CH=N), 8.25 (d, J = 8.8 Hz, 2H, H-8), 8.15 (s, 1H, H-3), 8.09 (d, J = 7.82 Hz, 2H, 4-tolyl), 7.86 (bs, 2H, H-5), 7.74 (d, J = 9.1 Hz, 2H, H-7), 7.46–7.40 (m, 2H, 4-tolyl), 7.34 (d, J = 7.8 Hz, 2H, C6H4OH), 7.06 (d, J = 8.3 Hz, 1H, C6H4OH), 6.97 (t, J = 7.4 Hz, 2H, C6H4OH), 2.44 (s, 3H, H-CH3); 13C NMR (151 MHz, CDCl3) δ 164.04 (CH=N), 161.29 (C6H4OH), 156.18 (C-2), 148.10 (C-8a), 147.44 (C-6), 140.47 (4-CH3-C6H4), 135.38 (4-tolyl), 134.75 (q, J = 31.5 Hz, C-4), 133.82 (C6H4OH), 132.74 (C6H4OH), 131.92 (C-8), 129.83 (4-tolyl), 127.30 (4-tolyl), 125.04 (C-7), 123.59 (q, J = 274.7 Hz, CF3), 122.37 (C-4a), 119.34 (C6H4OH), 119.10 (C6H4OH), 117.44 (C6H4OH), 116.40 (q, J = 7.3 Hz, C-3), 114.80 (C-5), 21.42 (4-CH3C6H4); 19F NMR (565 MHz, CDCl3) δ −61.65 (CF3); FTIR (ATR) ν: 3035 (ν OH), 1621 (ν CH=N), 1112 (ν C-O) cm−1; HRMS–ESI (m/z): [M + H]+ calcd for C24H17F3N2O, 407.1366; found, 407.1365.
(E)-2-(((2-(4-Fluorophenyl)-4-(trifluoromethyl)quinolin-6-yl)imino)methyl)phenol (3da): Yellow solid, yield 91%; mp 188–189 °C; 1H NMR (600 MHz, CDCl3) δ 12.91 (s, 1H, OH), 8.74 (s, 1H, CH=N), 8.27 (d, J = 9.0 Hz, 1H, H-8), 8.23–8.18 (m, 2H, 4-FC6H4), 8.14 (S, 1H, H-3), 7.89 (p, J = 2.0 Hz, 1H, H-5), 7.76 (dd, J = 8.9, 2.3 Hz, 1H, H-7), 7.49–7.42 (m, 2H, 4-FC6H4), 7.29–7.21 (m, 2H, C6H4OH), 7.09 (dd, J = 8.3, 1.1 Hz, 1H, C6H4OH), 7.00 (td, J = 7.5, 1.1 Hz, 1H, C6H4OH) ppm; 13C NMR (151 MHz, CDCl3) δ 164.25 (d, J = 250.8 Hz, 4-FC6H4), 164.13 (CH=N), 161.33 (C6H4OH), 154.97 (C-2), 148.03 (C-8a), 147.74 (C-6), 134.99 (q, J = 31.6 Hz, C-4), 134.31 (d, J = 3.6 Hz, 4-FC6H4), 133.86 (C6H4OH), 132.72 (C6H4OH), 131.92 (C-8), 129.32 (d, J = 8.7 Hz, 4-F-C6H4), 125.22 (C-7), 123.51 (q, J = 274.3 Hz, CF3), 122.39 (C-4a), 119.31 (C6H4OH), 119.07 (C6H4OH), 117.44 (C6H4OH), 116.17–115.85 (m) (3, 4-FC6H4), 114.67 (d, J = 2.2 Hz, C-5) ppm; 19F NMR (565 MHz, CDCl3) δ −61.67 (CF3), −110.77 (4-FC6H4) ppm; FTIR (ATR) ν: 3076 (ν OH), 1629 (ν CH=N), 1011 (ν C-O) cm−1; HRMS–ESI) (m/z): [M + H]+ calcd for C23H14F4N2O, 411.1115; found, 411.1119; Anal. calcd for C23H14F4N2O: C, 67.32; H, 3.44; N, 6.83; found: C, 67.18; H, 3.06; N, 6.97.
(E)-2-(((2-(4-Nitrophenyl)-4-(trifluoromethyl)quinolin-6-yl)imino)methyl)phenol (3ea): Orange solid, yield 65%; mp 223–226 °C; 1H NMR (600 MHz, CDCl3) δ 12.85 (s, 1H, OH), 8.77 (s, 1H, CH=N), 8.41 (s, 4H, 4-NO2C6H4), 8.34 (d, J = 8.7 Hz, 1H, H-8), 8.24 (s, 1H, H-3), 7.91 (s, 1H, H-5), 7.84 (dd, J = 8.9, 2.3 Hz, 1H, H-7), 7.53–7.41 (m, 2H, C6H4OH), 7.08 (d, J = 8.3 Hz, 1H, C6H4OH), 7.01 (t, J = 7.4 Hz, 1H, C6H4OH) ppm; 13C NMR (100 MHz, CDCl3) δ 164.71 (CH=N), 161.29 (C6H4OH), 153.41 (C-2), 148.72 (d, J = 3.6 Hz, C-8a, C-6), 148.03 (4-NO2C6H4), 143.81 (4-NO2C6H4), 135.45 (q, J = 32.4 Hz, C-4), 134.14 (C6H4OH), 132.87 (C6H4OH), 132.30 (C-8), 128.23 (4-NO2C6H4), 125.92 (C-7), 124.24 (4-NO2C6H4), 123.31 (q, J = 275.0 Hz, CF3), 123.08 (C-4a), 119.46 (C6H4OH), 118.96 (C6H4OH), 117.48 (C6H4OH), 116.33 (q, J = 5.2 Hz, C-3), 114.64 (C-5) ppm; 19F NMR (565 MHz, CDCl3) δ −61.66 (CF3); FTIR (ATR) ν: 3085 (ν OH), 1625 (ν CH=N), 1113 (ν C-O) cm−1; HRMS–ESI (m/z): [M + H]+ calcd for C23H15F3N3O3, 438.1060; found, 438.1059.
(E)-2-(((2-(Furan-2-yl)-4-(trifluoromethyl)quinolin-6-yl)imino)methyl)phenol (3fa): Brown solid, yield 80%; mp 205–209 °C; 1H NMR (600 MHz, CDCl3) δ 12.95 (s, 1H, OH), 8.74 (s, 1H, CH=N), 8.23 (dd, J = 9.0, 0.5 Hz, 1H, H-8), 8.13 (d, J = 0.8 Hz, 1H, H-3), 7.85 (p, J = 2.0 Hz, 1H, H-5), 7.75 (dd, J = 9.0, 2.3 Hz, 1H, H-7), 7.66 (dd, 3J = 1.7, 4J = 0.8 Hz, 1H, H-5” furyl), 7.49–7.39 (m, 2H, C6H4OH), 7.30 (dd, 3J = 3.5, 4J = 0.8 Hz, 1H, H-3” furyl), 7.08–7.04 (m, 1H, C6H4OH), 6.98 (td, J = 7.5, 1.1 Hz, 1H, C6H4OH), 6.63 (dd, 3J = 3.5, 3J = 1.8 Hz, 1H, H-4” furyl) ppm; 13C NMR (151 MHz, CDCl3) δ 164.11 (CH=N), 161.28 (C6H4OH), 152.75 (C-2), 147.97 (d, J = 3.7 Hz, C-6, C-8a), 147.52 (furyl), 144.82 (furyl), 134.96 (t, J = 31.9 Hz, C-4), 133.88 (C6H4OH), 132.76 (C6H4OH), 131.58 (C-8), 125.31 (C-7), 123.37 (q, J = 275.0 Hz, CF3), 122.38 (C-4a), 119.37 (C6H4OH), 119.08 (C6H4OH), 117.44 (C6H4OH), 115.40 (q, J = 5.6 Hz, C-3), 114.96 (d, J = 3.1 Hz, C-5), 112.67 (furyl), 111.28 (furyl) ppm; 19F NMR (565 MHz, CDCl3) δ −61.82 (CF3) ppm; FTIR (ATR) ν: 3066 (ν OH), 1612 (ν CH=N), 1121 (ν C-O) cm−1; HRMS–ESI (m/z): [M + H]+ calcd for C21H13F3N2O2, 383.1002; found, 383.0997.
(E)-5-(Diethylamino)-2-(((2-phenyl-4-(trifluoromethyl)quinolin-6-yl)imino)methyl)phenol (3bb): Orange solid, yield 40%; mp 208–210 °C; 1H NMR (600 MHz, CDCl3) δ 13.43 (s, 1H, OH), 8.53 (s, 1H, CH=N), 8.22 (d, J = 9.0 Hz, 1H, H-8), 8.18 (d, J = 7.4 Hz, 2H, Ph), 8.14 (s, 1H, H-3), 7.81 (p, J = 2.2 Hz, 1H, H-5), 7.72 (dd, J = 9.0, 2.3 Hz, 1H, H-7), 7.55–7.51 (m, 2H, Ph), 7.49–7.45 (m, 1H, Ph), 7.22–7.19 (m, 1H, 5-NEt2-C6H3OH), 6.27 (dd, J = 8.8, 2.5 Hz, 1H, 5-NEt2C6H3OH), 6.22 (d, J = 2.4 Hz, 1H, 5-NEt2C6H3OH), 3.41 (q, J = 7.1 Hz, 4H, (N-(CH2CH3)2), 1.22 (t, J = 7.1 Hz, 6H, (N-(CH2CH3)2) ppm; 13C NMR (151 MHz, CDCl3) δ 164.11 (CH=N), 161.79 (5-NEt2C6H3OH), 155.33 (C-2), 152.43 (5-NEt2C6H3OH), 148.59 (C-8a), 147.69 (C-6), 138.50 (Ph), 134.48 (q, J = 31.1 Hz, C-4), 134.26 (5-NEt2C6H3OH), 131.74 (C-8), 129.83 (Ph), 128.98 (Ph), 127.33 (Ph), 125.69 (C-7), 123.75 (q, J = 274.7 Hz, CF3), 122.81 (C-4a), 116.24 (q, J = 5.6, 5.2 Hz, C-3), 113.45 (C-5), 109.37 (5-NEt2C6H3OH), 104.26 (5-NEt2C6H3OH), 97.87 (5-NEt2C6H3OH), 44.66 ((N-(CH2CH3)2), 12.72 (N-(CH2CH3)2) ppm; 19F NMR (565 MHz, CDCl3) δ −61.73 (CF3) ppm; FTIR (ATR) ν: 2974 (ν OH), 1638 (ν CH=N), 1117 (ν C-O) cm−1; HRMS–ESI (m/z): [M + Na]+ calcd for C27H24F3N3NaO, 486.1764; found, 486.1727; Anal. calcd for C27H24F3N3O: C, 69.97; H, 5.22; N, 9.07; found: C, 69.50; H, 5.09; N, 9.26.
(E)-5-Methoxy-2-(((2-phenyl-4-(trifluoromethyl)quinolin-6-yl)imino)methyl)phenol (3bc): Orange solid, yield 75%; mp 226–230 °C; 1H NMR (600 MHz, CDCl3) δ 13.34 (s, 1H, OH), 8.64 (s, 1H, CH=N), 8.26 (d, J = 8.9 Hz, 1H, H-8), 8.23–8.11 (m, 3H, 2H, Ph, H-3), 7.85 (bs, 1H, H-5), 7.76–7.69 (m, 1H, H-7), 7.52 (dt, J = 14.2, 7.1 Hz, 3H, Ph), 7.33 (d, J = 8.4 Hz, 1H, 5-OCH3C6H3OH), 6.53 (d, J = 8.8 Hz, 2H, 5-OCH3C6H3OH), 3.86 (s, 3H, OCH3) ppm; 13C NMR (151 MHz, CDCl3) δ 164.70 (CH=N), 164.03 (5-OCH3C6H3OH), 162.99 (5-OCH3C6H3OH), 155.99 (C-2), 148.01 (d, J = 3.8 Hz, C-6, C-8a), 138.38 (Ph), 134.82 (d, J = 31.5 Hz, C-4), 134.05 (5-OCH3C6H3OH), 132.01 (C-8), 130.05 (Ph), 129.05 (Ph), 127.42 (Ph), 125.35 (C-7), 123.69 (q, J = 274.7 Hz, CF3), 122.68 (C-4a), 116.46 (q, J = 4.9 Hz, C-3), 114.26 (C-5), 113.23 (5-OCH3C6H3OH), 107.60 (5-OCH3C6H3OH), 101.28 (5-OCH3C6H3OH), 55.52 (OCH3) ppm; 19F NMR (565 MHz, CDCl3) δ −61.74 (CF3) ppm; FTIR (ATR) ν: 3016 (ν OH), 1628 (ν CH=N), 1000 (ν C-O) cm−1; HRMS–ESI (m/z): [M + H]+ calcd for C24H17F3N2O2, 423.1315; found, 423.1284.
(E)-4-Bromo-2-(((2-phenyl-4-(trifluoromethyl)quinolin-6-yl)imino)methyl)phenol (3bd): Orange solid, yield 77%; mp 194–196 °C; 1H NMR (600 MHz, CDCl3) δ 12.86 (s, 1H, OH), 8.63 (s, 1H, CH=N), 8.27 (d, J = 9.0 Hz, 1H, H-8), 8.19 (d, J = 7.0 Hz, 3H, 2H Ph, H-3), 7.89–7.84 (m, 1H, H-5), 7.72 (dd, J = 9.0, 2.3 Hz, 1H, H-7), 7.57–7.44 (m, 5H, 3H, Ph, 2H, 4-BrC6H3OH), 6.94 (d, J = 8.8 Hz, 1H, 4-BrC6H3OH) ppm; 13C NMR (151 MHz, CDCl3) δ 162.68 (CH=N), 160.34 (4-BrC6H3OH), 156.48 (C-2), 148.32 (C-8a), 147.18 (C-6), 138.15 (Ph), 136.39 (4-BrC6H3OH), 135.02 (q, J = 31.5 Hz, C-4), 134.64 (4-BrC6H3OH), 132.22 (C-8), 130.22 (Ph), 129.06 (Ph), 127.44 (Ph), 124.89 (C-7), 123.59 (q, J = 274.3 Hz, CF3), 122.49 (C-4a), 120.49 (4-BrC6H3OH), 119.45 (4-BrC6H3OH), 116.60 (q, J = 5.4 Hz, C-3), 114.92 (d, J = 2.4 Hz, C-5), 110.80 (4-BrC6H3OH) ppm; 19F NMR (565 MHz, CDCl3) δ −61.63 (CF3) ppm; FTIR (ATR) ν: 3060 (ν OH), 1602 (ν CH=N), 1112 (ν C-O) cm−1; HRMS–ESI (m/z): [M + H]+ calcd for C23H14BrF3N2O, 471.0314; found, 471.0314; Anal. calcd for C23H14BrF3N2O: C, 58.62; H, 2.99; N, 5.94; found: C, 58.04; H, 2.73; N, 6.26.
(E)-4-Nitro-2-(((2-phenyl-4-(trifluoromethyl)quinolin-6-yl)imino)methyl)phenol (3be): Orange solid, yield 89%; mp 253–256 °C; 1H NMR (600 MHz, CDCl3) δ 14.01 (s, 1H, OH), 8.85 (s, 1H, CH=N), 8.48 (d, J = 2.7 Hz, 1H, 4-NO2C6H3OH), 8.35 (d, J = 9.0 Hz, 1H, H-8), 8.33–8.30 (m, 1H, 4-NO2C6H3OH), 8.25–8.19 (m, 3H, H-3, Ph), 7.95 (bs, 1H, H-5), 7.81 (dd, J = 8.9, 2.3 Hz, 1H, H-7), 7.58 (t, J = 7.3 Hz, 2H, Ph), 7.53 (t, J = 7.2 Hz, 1H, Ph), 7.16 (d, J = 9.1 Hz, 1H, 4-NO2C6H3OH) ppm; 13C NMR (151 MHz, CDCl3) δ 166.49 (CH=N), 162.31 (4-NO2C6H3OH), 156.92 (C-2), 148.46 (C-8a), 146.05 (C-6), 140.26 (4-NO2C6H3OH), 137.97 (Ph), 135.14 (q, J = 30.5 Hz, C-4), 132.44 (C-8), 130.39 (Ph), 129.14 (Ph), 128.86 (4-NO2C6H3OH), 128.74 (4-NO2C6H3OH), 127.47 (Ph), 124.52 (C-7), 123.43 (q, J = 274.9 Hz, C-CF3), 122.42 (C-4a), 118.45 (4-NO2C6H3OH), 118.11 (4-NO2C6H3OH), 116.86 (q, J = 5.4 Hz, C-3), 115.55 (C-5) ppm; 19F NMR (565 MHz, CDCl3) δ −61.57 (CF3); FTIR (ATR) ν: 3072 (ν OH), 1602 (ν CH=N), 1125 (ν C-O) cm−1; HRMS–ESI (m/z): [M + H]+ calcd for C23H14F3N3O3, 438.1060; found, 438.1063.
|Supporting Information File 1: NMR spectra of the compounds, IR spectra, crystallographic data, photophysical and singlet oxygen spectra of new structures.|
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We would like to thank the following entities: The Coordination for Improvement of Higher Education Personnel (CAPES/PROEX – Finance Code 001) for the fellowships, and the National Council for Scientific and Technological Development (CNPq) (grants process Grants no. 305.379/2020-8) and the Research Support Foundation of the State of Rio Grande do Sul (FAPERGS) (PqG, process no. 17/2551-0001275-5) for financial support. Bernardo A. Iglesias thanks also CNPq; Universal process no. 409.150/2018-5 and grants process no. 304.711/2018-7.