One-Pot Synthesis of 2,3,4-Triarylquinolines via Suzuki-Miyaura Cross-Coupling of 2-Aryl-4-chloro-3-iodoquinolines with Arylboronic Acids

Palladium–catalyzed Suzuki cross-coupling of 2-aryl-4-chloro-3-iodoquinolines with excess arylboronic acids (2.5 equiv.) in the presence of tricyclohexylphosphine afforded the 2,3,4-triarylquinolines in one-pot operation. The incipient 2,3-diaryl-4-chloroquinolines were also prepared and transformed to the primary 4-amino-2,3-diarylquinolines and 2,3-diarylquinolin-4(1H)-ones.


OPEN ACCESS
chloroquinolines in moderate yields [1]. Hitherto our investigation, the analogous 4-chloro-6-(bromo/iodo)quinolines were subjected to successive replacement of the two halogen atoms via Suzuki cross-coupling to afford the Csp 2 -Csp 2 cross-coupled products [2,3]. The second arylboronic acid was in this case added to the reaction mixture after completion of the first step (tlc monitoring) without isolating the incipient 6-substituted derivative. Despite the successes in sequential metal-catalyzed halogen substitution reactions [2][3][4], the development of versatile and efficient methods for the synthesis of polysubstituted quinolines from dihaloquinolines in a single operation remains a challenge in organic synthesis. We are interested in the synthesis of 3,4-disubstituted 2-arylquinoline derivatives as a prelude to derivatives with potential biological activity or photoelectronic properties and the 2aryl-4-chloro-3-iodoquinolines appeared suitable candidates for palladium-catalyzed Suzuki crosscoupling to afford such systems.
To further demonstrate the versatility of the 4-chloroquinoline derivatives in synthesis in the last part of this investigation, we decided to investigate the possibility of transforming systems 2e-f to the NH-4-oxo derivatives. Whereas the NMe-4-oxo [22] or NPh-4-oxo [23] derivatives undergo Suzuki cross-coupling with arylboronic acids with ease to afford the corresponding N-substituted 2,3diarylquinolinones, under similar reaction conditions the NH-4-oxo precursors afford complex mixtures of products [22]. Although demethylation of 2,3-diaryl-4-methoxyquinolines with boron tribromide in dichloromethane afforded the 2,3-diarylquinolin-4(1H)-ones, under these reaction conditions the 4-methoxy-2-(4-methoxyphenyl)-3-phenylquinoline led to a complex mixture of products lacking the methoxy signals in the 1 H-NMR spectrum [1]. Consequently, in this investigation we subjected systems 2e-h to acetic acid/water (4:1, v/v) under reflux and we isolated the corresponding previously undescribed 2-aryl-3-(4-fluorophenyl)quinolin-4(1H)-ones 5a-d in high yield and purity (Scheme 3). The smooth hydrolysis of the 4-chloroquinolines to afford the NH-4-oxo derivatives without affecting the 4-methoxy group make this a convenient synthetic strategy for the construction of 2,3-diarylquinolin-4(1H)-ones that are difficult to synthesize otherwise.

General
Melting points were recorded on a Thermocouple digital melting point apparatus. IR spectra were recorded as powders using FTS 7000 Series Digilab Win-IR Pro ATR (attenuated total reflectance) spectrometer. For column chromatography, Merck Kieselgel 60 (0.063-0.200 mm) was used as stationary phase. NMR spectra were obtained using a Varian Mercury 300 MHz NMR spectrometer and the chemical shifts are measured relative to the solvent peaks. Low and high-resolution mass spectra were recorded at an ionization potential of 70eV using a Micromass Autospec-TOF (double focusing high resolution) instrument. The synthesis and characterization of substrates 1 have been described before [1].

Synthesis of 2-aryl-4-chloro-3-(4-fluorophenyl)quinolines 2e-h. typical procedure
A mixture of 2-aryl-4-chloro-3-iodoquinoline 1 (1 equiv.), arylboronic acid (1.2 equiv.) and Pd(PPh 3 ) 4 (5% of 1) in DMF (5 mL/mmol of 1) in a two-necked flask equipped with a stirrer bar, rubber septum and a condenser was flushed with nitrogen gas. After 10 minutes 2M K 2 CO 3 (2 mL/mmol of 1) was added and the mixture was flushed for additional 10 minutes with nitrogen gas. A balloon filled with nitrogen gas was connected to the top of the condenser and the mixture was heated with stirring at 80-90 °C for 48 hours. The mixture was allowed to cool to room temperature and then quenched with ice-cold water. The product was extracted with chloroform and the combined organic extracts were washed with brine, dried over anhydrous MgSO 4 , filtered and then evaporated under reduced pressure. The residue was purified by column chromatography to afford the 2-aryl-4chloro-3-(4-fluorophenyl)quinoline 2. The following products were prepared:  124.7, 125.5, 128.0, 128.1, 129.9, 130.6, 131.1, 131.8

Reaction of 2e-h with aniline. typical procedure
A mixture of 2 (1 equiv.) and aniline (2.5 equiv.) was heated under reflux for 18 hours. The cooled mixture was quenched with ice-cold water and then extracted with chloroform. The combined organic phase was dried over MgSO 4 , filtered and then evaporated under reduced pressure. The residue was purified by column chromatography to afford (4).

Hydrolysis of 4 with acetic acid: typical procedure
A suspension of 2 (1 equiv.) in acetic acid-water (5:1, v/v) was refluxed for 6 hours. The mixture was quenched with ice-cold water and the precipitate was filtered and recrystallized to afford 5.

Crystal Structure Solution and Refinement
X-ray quality crystals of the title compound 3f were obtained by slow crystallization from ethanol solution. Intensity data were collected on a Bruker APEX II CCD area detector diffractometer with graphite monochromated Mo K α radiation (50 kV, 30 mA) using the Bruker APEX 2 [30] data collection software. The collection method involved ω-scans of width 0.5° and 512 × 512 bit data frames. Data reduction was carried out using the program Bruker SAINT+ [31]. The crystal structure was solved by direct methods using Bruker SHELXTL [32]. Non-hydrogen atoms were first refined isotropically followed by anisotropic refinement by full matrix least-squares calculations based on F 2 using SHELXTL. Hydrogen atoms were first located in the difference map then positioned geometrically and allowed to ride on their respective parent atoms. Diagrams and publication material were generated using SHELXTL, PLATON [33] and ORTEP-3 [34].

Conclusions
Overall, the results described in this investigation present another example showing the potential of 2-aryl-4-chloroquinolines in the synthesis of novel 2,3,4-trisubstituted quinolines and the 2,3diarylquinolin-4(1H)-ones with potential to serve as molecular organic materials in nanomaterials or as selective cyclooxygenase-1/-2 (COX-1/-2) inhibitors. Polyarylquinoline-based compounds constitute an important component in optoelectronic materials [24][25][26]. This moiety constitutes a π-conjugated bridge in nonlinear optical polymers [27] and also serves as electron-acceptor unit in carbazole-quinoline and phenothiazine-quinoline copolymers and oligomers found to exhibit intramolecular charge transfer [28]. The 2,3,4-triarylquinoline derivatives prepared in this investigation can also serve as substrates for metalation with iridium, for example, to form cyclometalated iridium complexes with potential application in organic light-emitting diodes (OLEDs) [25,26] or novel red-emitting electrophosphorescent devices [29]. Studies are currently underway in our laboratory to investigate the biological and photophysical properties of the polysubstuituted quinolones and their quinoline derivatives.