N-Arylation of 3-Formylquinolin-2(1H)-ones Using Copper(II)-Catalyzed Chan–Lam Coupling

3-formyl-2-quinolones have attracted the scientific community’s attention because they are used as versatile building blocks in the synthesis of more complex compounds showing different and attractive biological activities. Using copper-catalyzed Chan–Lam coupling, we synthesized 32 new N-aryl-3-formyl-2-quinolone derivatives at 80 °C, in air and using inexpensive phenylboronic acids as arylating agents. 3-formyl-2-quinolones and substituted 3-formyl-2-quinolones can act as substrates, and among the products, the p-methyl derivative 9a was used as a substrate to obtain different derivatives such as alcohol, amine, nitrile, and chalcone.


Introduction
The N-arylation of N-heterocyclic compounds has made a great impact on the advance of organic chemistry. This coupling reaction has simplified the generation of new derivatives with a wide range of applications due to their biological [1][2][3], agrochemical, photophysical [4][5][6], and catalytic [7] properties, among others. In this regard, since the last century, the Ullman-Goldberg and Buchwald-Hartwig cross-coupling reactions have played relevant roles using aryl halides for the N heterocycle -C aryl bond formation [8]. However, these synthetic methods have several drawbacks, such as the use of expensive metal catalysts, toxic solvents, ligands that are not commercially available, or harsh reaction conditions, and, for this reason, new alternatives have been emerging [9,10].
In this sense, the Chan-Lam cross-coupling reaction offers a viable alternative for generating C aryl -heteroatom bonds, especially in the arylation of N-heterocyclic compounds [11]. This protocol consists of the substitution of an aryl boronic acid with different nucleophiles (especially N-H, O-H, S-H, and P-H) in the presence of a copper catalyst under mild reaction conditions (e.g., under air, at room temperature) [12]. Thanks to these characteristics, the N-arylation of heterocyclic compounds employing this methodology has become more frequent in the last decade. In particular, the N-arylation of pyrroles [13], purines [14] and triazoles [15] is noteworthy and, most recently, the derivatization of a natural product with the N-arylation of the quinolizidine alkaloid cytisine has been shown [16].
The N-arylation of quinolines, and specifically their 2-oxo derivatives (2-quinolones) 1, is an emerging area; these N-heterocycles are important structural constituents of numerous naturally occurring compounds [17], and represent relevant synthetic scaffolds for the generation of compounds with interesting or useful biological properties,

Results and Discussion
The preparation of 3-formylquinolones was carried out according to the methodology reported by Meth-Cohn et al. [58] (Scheme 2). The first step consisted of the acetylation of the commercial anilines 4a-e with acetic anhydride to obtain the respective acetanilides, 5a-e. Cyclization and hydroformylation (in situ) were carried out using the Vilsmeier-Haack reagent, producing the 2-chloro-3-formylquinolines 6a-e. The final step cor-

Results and Discussion
The preparation of 3-formylquinolones was carried out according to the methodology reported by Meth-Cohn et al. [58] (Scheme 2). The first step consisted of the acetylation of the commercial anilines 4a-e with acetic anhydride to obtain the respective acetanilides, 5a-e. Cyclization and hydroformylation (in situ) were carried out using the Vilsmeier-Haack reagent, producing the 2-chloro-3-formylquinolines 6a-e. The final step corresponded to acid hydrolysis mediated by 70% acetic acid, which lead to 3-formyl-2-quinolone 7a-e precursors in moderate-to-good yields.

Results and Discussion
The preparation of 3-formylquinolones was carried out according to the methodology reported by Meth-Cohn et al. [58] (Scheme 2). The first step consisted of the acetylation of the commercial anilines 4a-e with acetic anhydride to obtain the respective acetanilides, 5a-e. Cyclization and hydroformylation (in situ) were carried out using the Vilsmeier-Haack reagent, producing the 2-chloro-3-formylquinolines 6a-e. The final step corresponded to acid hydrolysis mediated by 70% acetic acid, which lead to 3-formyl-2-quinolone 7a-e precursors in moderate-to-good yields. Our research began with optimization of the synthetic process; we used 3-formylquinolone 7a as the substrate, 4-methylphenylboronic acid 8a as the arylating agent, 10 mmol % Cu(OA) 2 as the catalyst, a 3 Å molecular sieve, triethylamine (TEA) as the base, and acetonitrile as the solvent. The entire system was heated at 80 • C for 24 h, but no product formation was observed (Table 1, entry 1). The reason for starting with reagent 8a, due to the presence of methyl in the para (p) position, is the generation of an activation in the aromatic ring (electron donor by inductive effect) which can give better performance; this has been evidenced in early reports by the Chan and Lam groups that demonstrated the N-arylation of a wide range of N-heterocyclic substrates using p-methylphenylboronic acid [59]. Furthermore, Janíková et al. reported this acid as a standardization material for Chan-Lam-type N-arylation when N-heterocyclic systems with carbonyl groups adjacent to an -NH group are involved [60]. On the other hand, the low solubility of the compound 7a in CH 2 Cl 2 led us to start the standardization with acetonitrile at 80 • C. In turn, the copper salt was not used in stoichiometric amounts since the purpose of this research was to find a protocol where copper is used in catalytic amounts. Lastly, TEA was used as the base, as it is inexpensive, readily available, and according to previous reports, has proved to be exceptionally effective for Chan-Lam coupling between quinolones and phenylboronic acids [61]. However, due to our initial results, we decided to change the base to pyridine, even though at first no arylation product was observed ( Table 1, entry 2). Because the low solubility of 7a in acetonitrile was thought to affect the reaction, the solvent was changed to DMSO, with TEA as the base. Unfortunately, no conversion of the starting material was observed (Table 1, entry 3). For this reason, we tried pyridine again, and obtained the N-arylated product 9a in a modest 15% yield (Table 1, entry 4).   To improve the yield, we changed the solvent to DMF to increase 7a solubility. TEA was used again, and the yield of the N-arylated quinolone 9a rose to 58% (Table 1, entry 5). Motivated by this result, we began to analyze the base's effect in this protocol; therefore, different base substances commonly used in Chan-Lam cross-couplings were tried, but the results were similar or even worse than those seen for TEA (Table 1, entries 6-13). Nevertheless, when pyridine was used as the base and DMF as the solvent, the yield rose to 60% (Table 1, entry 14). In addition, using 3 Å molecular sieves, we obtained the best yield to the N-arylated product 9a, 64% (Table 1, entry 15). This indicates that, in our system, the presence of water led to a possible competition with the Chan-Lam C-O bond formation [62]. In order to improve the yield of product 9a, the same reaction conditions mentioned above were explored (Table 1, entry 15), and the reaction time extended up to 48 h; however, the yield of product 9a did not exceed 64% (Table 1, entry 16). Therefore, it was decided to increase the amount of catalyst to 20 mol%; however, the yield of compound 9a decreased to 47% (Table 1, test 17). Furthermore, Bipy and TMDA were included as copper ligands (Table 1, entries 18 and 19), but there was no benefit whatsoever. Finally, different Cu(II) salts (Cu (OTf) 2 , CuBr 2 and CuCl 2 ) were used in the hope that they would improve the quality of the proposed protocol (Table 1, entries 20-22); unfortunately, they were less effective.
It should be noted that 3-formylquinolone systems are tautomerizable heterocycles [63], and because of this, there is the possibility that the Chan-Lam reaction forms O-aryl or N-aryl bonds, as has been reported with other methodologies [64]. To demonstrate N-C aryl bond formation, 9a was crystallized by slow diffusion at room temperature in a mixture of dichloromethane-ethyl acetate (10:1), and the crystal structure was analyzed using single-crystal X-ray diffraction [CCDC 2205662]. This technique confirmed the structure of the compound, proving that the proposed protocol is selective towards the generation of N-aryl-3-formylquinolones ( Figure 1).
Subsequently, different halogenated phenylboronic acids replaced at the metaand para-positions were used. Starting from the meta-F, Cl, Br and CF 3 -substituted precursors, the fluoro-derivative 9f (15%) was obtained with a yield higher than 10%; unfortunately, meta-substituted derivatives with Cl, Br, I, CF 3 and OCF 3 did not appear in yields greater than 10%. To improve the yields of 9g-k, we opted to analyze the reaction mixtures and found that the main side products were the homocoupled phenylboronic acids. Taking this into account, we decided to add the base and the corresponding phenylboronic acids in portions (0.4 equivalents of each), separated by 90 min over a reaction time of 24 h. Using this methodology for the least satisfactory cases, the yields of the products 9g, 9h, and 9j rose to 45, 41 and 34%, respectively.
On the other hand, the para-substituted series provided yields that ranged between 18-35%, the derivative 9q being the one with the highest transformation (36%) and those with the least, 9s and 9t (both 18%), being, now, the analogs 9p, 9r and 9u and reflected yields of 35%, 30% and 20%, respectively. The decrease in yield on changing from parato meta-halo derivatives was attributed to the slight increase in acidity and the electronic effect caused by halogens at the meta position of the phenylboronic acids, leading to side reactions [65].
In the same context, considering both substitution positions, the yields decreased when changing from fluoro to iodo, CF 3 and OCF 3 , as a result of the electronic effects of these atoms on the acidity of the phenylboronic acid, which leads to byproducts generated by prodeboronation [16,62]. Furthermore, N-phenyl derivatives could be obtained with electron-withdrawing groups on the phenyl ring at the metaand para-substitutions: methoxycarbonyl gave the meta-substitution product 9l (19%) and the para-substituted 9v (23%), while the formyl group at the meta or para substitution generated 9m (24%) and 9w (22%), respectively. Finally, with 2-naphthylboronic acid, 9x was obtained in 23% yield.
The reaction yields shown in Table 2 apparently depend on the electronic properties and the position of substituents on the aromatic ring of the phenylboronic acid. When there is an electron-donating group in the aromatic system, the reaction yield is higher, in accordance with other Chan-Lam cross-coupling derivatization reports [62,66]. In the same way, the position of the substituent is of great importance. In this case, the para-substituted fenilboronic acids give a better conversion towards the N-arylated derivative than the meta-substituted isomers. This is attributed to the slight increase in acidity presented by the meta-substituted phenylboronic acids, since, through the mesomeric and inductive effects exerted by the substituents, the hydroxyborate anion (electrophile) is stabilized in comparison with the para-substituted acids [67]. As a consequence, the increased acidity can lead to the formation of undesired products such as phenols, and the oxidation of the aromatic system can lead to quinones [68][69][70] and protodeboronations [71].
It is worth mentioning that N-arylation of 3-formylquinolones with heteroaryl boronic acids or with o-substituted phenylboronic acids was not achieved (see Supplementary  Information). The N-arylated derivatives were not detected and, on the contrary, mixtures of byproducts or decomposition products were obtained. This could be related to the fact that heteroaryl boronic acids are prone to protodeboronations [71], and o-substituted phenylboronic acids can undergo intramolecular reactions leading to the formation of hydrogen donor-acceptor bonds that are decisive for the reaction [16,65,72].
To examine the versatility of this methodology, the N-arylation of various other 3formylquinolones (Table 3) was carried out employing phenylboronic acids with a methyl group or a fluorine atom at the para-substitution. The series consisted of four substituted 3-formylquinolones bearing a methyl group (7b) or a bromine atom (7c) at position 6-, and a methoxyl group (7d) or a chlorine atom (7e) at position 7-. With 6-methyl-3formylquinolone and p-methylphenylboronic acid, 10a was obtained in a 43% yield, and with p-fluorophenylboronic acid, 10b was produced in a 41% yield. On changing the methyl group to bromine at position 6-, the corresponding N-p-methylphenyl derivative 10c was obtained in a higher yield (57%). In contrast, the N-p-fluorophenyl derivative, 10d, was acquired in a lower yield (28%) compared with 10b. According to these results, it is clear that an electron-donating or electron-withdrawing group at position 6-in 3-formylquinolones affects the yield of Chan-Lam cross-couplings. Thus, ongoing from methyl (7b) to bromo (7c), the N-arylation with p-methylphenyl boronic acid increases, while it decreases with para-fluorophenylboronic acid. These results could be related to the quinolone's basicity, which drops when electron-withdrawing groups are contained in its structure. It is worth mentioning that N-arylation of 3-formylquinolones with heteroaryl boronic acids or with o-substituted phenylboronic acids was not achieved (see Supplementary Information). The N-arylated derivatives were not detected and, on the contrary, mixtures of byproducts or decomposition products were obtained. This could be related to Subsequently, 7-methoxy-3-formylquinolone, 7d, gave 10e (32%) and 10f (26%) with p-methoxyor p-fluorophenylboronic acids, respectively. Meanwhile, higher conversions were evidenced from 7-chloro-3-formylquinolone with the aforementioned acids, where the corresponding N-p-methylphenyl (10g) and N-p-fluorophenyl derivatives (10h), respectively, were obtained in 50% yield. It is important to highlight that upon exchanging an electron-donating group (at the 6-or 7-position) for a halogen, the yields of N-pmethylphenyl derivatives rise. Still, the location of this halogen, together with its electronic nature, could increase or decrease the conversion to the N-p-fluorophenyl derivatives.  Thanks to the abovementioned success, we proceeded to demonstrate the chemica reactivity of the coupling products. Therefore, Scheme 3 shows different chemical trans formations of the aldehyde group at position 3-in 9a. To establish the versatility of thi approach for later derivatizations, we began with a reduction of the aldehyde with NaBH in MeOH to obtain 11 in 83% yield. Then, the respective nitrile 12 was obtained in 88% yield under fast-heating conditions through a one-pot methodology mediated by "act vated" DMSO [75] with hydroxylammonium chloride in DMSO. Additionally, reductiv amination of 9a at room temperature with p-methoxybenzylamine in MeOH was carrie out to obtain product 13 in 99% yield. Finally, a Claisen-Schmidt type condensation a room temperature between 9a and 4-methoxyacetophenone, using NaOH (10% w/v, 0. mL) in MeOH as a solvent; this produced chalcone 14 in 83% yield. Thanks to the abovementioned success, we proceeded to demonstrate the chemica reactivity of the coupling products. Therefore, Scheme 3 shows different chemical trans formations of the aldehyde group at position 3-in 9a. To establish the versatility of this approach for later derivatizations, we began with a reduction of the aldehyde with NaBH in MeOH to obtain 11 in 83% yield. Then, the respective nitrile 12 was obtained in 88% yield under fast-heating conditions through a one-pot methodology mediated by "acti vated" DMSO [75] with hydroxylammonium chloride in DMSO. Additionally, reductive amination of 9a at room temperature with p-methoxybenzylamine in MeOH was carried out to obtain product 13 in 99% yield. Finally, a Claisen-Schmidt type condensation a room temperature between 9a and 4-methoxyacetophenone, using NaOH (10% w/v, 0.3 mL) in MeOH as a solvent; this produced chalcone 14 in 83% yield. With these results, it is clear that varying the electronic nature of the substituent at either the 6-or the 7-position of the 3-formylquinolone affects its basicity [73,74], and therefore has a direct repercussion on the conversion during the Chan-Lam cross-coupling. Notwithstanding, a clear trend is not yet discernible; for that purpose, further experiments should be assessed varying the substituents on the quinolone core. Thanks to the abovementioned success, we proceeded to demonstrate the chemical reactivity of the coupling products. Therefore, Scheme 3 shows different chemical transformations of the aldehyde group at position 3-in 9a. To establish the versatility of this approach for later derivatizations, we began with a reduction of the aldehyde with NaBH 4 in MeOH to obtain 11 in 83% yield. Then, the respective nitrile 12 was obtained in 88% yield under fast-heating conditions through a one-pot methodology mediated by "activated" DMSO [75] with hydroxylammonium chloride in DMSO. Additionally, reductive amination of 9a at room temperature with p-methoxybenzylamine in MeOH was carried out to obtain product 13 in 99% yield. Finally, a Claisen-Schmidt type condensation at room temperature between 9a and 4-methoxyacetophenone, using NaOH (10% w/v, 0.3 mL) in MeOH as a solvent; this produced chalcone 14 in 83% yield.
approach for later derivatizations, we began with a reduction of the aldehyde with NaBH4 in MeOH to obtain 11 in 83% yield. Then, the respective nitrile 12 was obtained in 88% yield under fast-heating conditions through a one-pot methodology mediated by "activated" DMSO [75] with hydroxylammonium chloride in DMSO. Additionally, reductive amination of 9a at room temperature with p-methoxybenzylamine in MeOH was carried out to obtain product 13 in 99% yield. Finally, a Claisen-Schmidt type condensation at room temperature between 9a and 4-methoxyacetophenone, using NaOH (10% w/v, 0.3 mL) in MeOH as a solvent; this produced chalcone 14 in 83% yield.

General Information
All solvents, including deuterated solvents, were purchased from Merck. Other reagents were from Aldrich, Merck or AK Scientific. Column chromatography was performed on silica gel (Merck, type 60, 0.063-0.2 mm). Melting points were determined on a Reichert Galen III hot plate microscope apparatus and were uncorrected. NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer. All chemical shifts in NMR experiments were reported as ppm downfield from TMS. The following calibrations were used: CDCl 3 δ = 7.26 and 77.0 ppm for 1 H NMR and 13 C NMR, respectively, and DMSO-d 6 δ = 2.50 ppm for 1 H NMR. Monowave-promoted reactions were performed in a Monowave 50 reactor (Anton Paar, Graz, Austria). HPLC-HR-MS experiments were carried out on an Exactive Plus Orbitrap MS instrument (Thermo Scientific, Waltham, MA, USA). The accurate mass measurements were performed at a resolution of 140,000.

Synthesis of 2-Chloroquinoline-3-carbaldehydes (6a-e)
These compounds were prepared by following the Meth-Cohn method [58]. DMF (11.6 mL, 150 mmol), in a round-bottom flask was cooled in an ice-water bath to 0.0-2.5 • C and phosphoryl chloride (32.2 mL, 350 mmol) was added dropwise with stirring. To this solution, the corresponding acetanilide (50 mmol) was added and the temperature of the reaction mixture was raised to 80 • C during 20 h. Finally, the mixture was poured into ice-water (300 mL) for 30 min. The precipitate formed was filtered off, washed with cold water and recrystallized from acetonitrile.