Direct One-Pot Synthesis of Primary 4-Amino-2,3-diaryl- quinolines via Suzuki-Miyaura Cross-Coupling of 2-Aryl-4-azido-3-iodoquinolines with Arylboronic Acids

Palladium-catalyzed Suzuki-Miyaura cross-coupling of 2-aryl-4-azido-3-iodo-quinolines with arylboronic acids afforded the corresponding primary 4-amino-2,3-diarylquinolines in a single-pot operation along with symmetrical biaryls and traces of the 2,3-diaryl-4-azidoquinolines. A plausible mechanism, which implicates palladium hydride species in the reduction of the incipient 2,3-diaryl-4-azidoquinolines to afford the 4-amino-2,3-diarylquinolines is proposed.

Despite the outcome of the above reaction, we were concerned about the low yields and prolonged reaction times, presumably due to the slow oxidative addition step using Pd(PPh 3 ) 4 as precursor of the palladium(0) complex. This slow oxidative addition step is attributed to the inhibiting role of the extra PPh 3 generated in the second equilibrium {SPd(0)(PPh 3 ) 3 SPd(0)(PPh 3 ) 2 + PPh 3 (K 2 /[PPh 3 ] << 1); S = solvent} to afford the low reactivity ligated 14-electron species (Pd(0)(PPh 3 ) 2 ) [24]. Conversely, the oxidative addition performed by the palladium(0) complex (Pd(0)(PPh 3 ) 2 Cl − ) generated by the reduction of dichlorobis(triphenylphosphine)palladium(II) (PdCl 2 (PPh 3 ) 2 ) is reported to be more than 30 times faster than that performed from Pd(0)(PPh 3 ) 4 [24]. Likewise, alkylphosphine ligands are known to coordinate with palladium and increase its electron density more than arylphosphines and, in turn, accelerate the oxidative addition and reductive elimination steps in the catalytic cycle [27,28]. Consequently, we subjected substrates 1a-d to 2 equiv. of phenylboronic acid in the presence of PdCl 2 (PPh 3 ) 2 -tricyclohexylphosphine (PCy 3 ) catalyst mixture and 2 M potassium carbonate in DMF under reflux (Scheme 1). The reaction in the presence of PdCl 2 (PPh 3 ) 2 -PCy 3 catalyst mixture was complete within 18 h. Analysis of the crude product mixtures by thin layer chromatography revealed in all cases three spots of different polarity and intensity with no traces of the spot corresponding to the starting material. The mixture was isolated by column chromatography on silica gel to afford the biphenyl 2a, 4-azido-2,3-diarylquinolines 3a-d (minor) and 4-amino-2,3-diarylquinolines 4a-d (major) in sequence. The reaction conditions were also extended to include 4-fluorophenylboronic and 4-methoxyphenylboronic acids as coupling partners. Although in all cases, traces of the 4-azido-2,3diarylquinolines 3 (2nd spot) were detected by thin layer chromatography in the crude product mixture, careful column chromatographic separation on silica gel in most cases led to isolation of the self-coupled biaryl derivatives 2b,c (minor) and the 4-amino-2,3-diarylquinolines 4a-l as the major products.  (2c)   12  16  10  11  -------9   57  65  54  66  65  66  56  64  63  57  60  68 At first glance, we also thought products 4 are the result of the initial cross-coupling of 1 with arylboronic acids and subsequent in situ Staudinger reaction of the 2,3-diaryl-4-azidoquinolines 3 with PPh 3 released from the catalyst followed by hydrolysis of the incipient 2,3-diaryl-4-(triphenylphosphoranylideneamino)quinolones, in analogy with the previous literature observation [20]. However, this possibility was ruled out by the absence of triphenylphosphonium oxide in the reaction mixture or crude product (tlc monitoring or 31 P-NMR), which is the expected by-product of hydrolysis of phosphazene derivatives [18]. Recourse to literature, revealed a paper describing the results of palladium acetate (Pd(OAc) 2 )-catalyzed Suzuki-Miyaura cross-coupling of nitroaryl halides with arylboronic acids in DMF/H 2 O at 150 °C using K 2 CO 3 as a base in the absence or presence of a ligand (PPh 3 or DABCO) [29]. The reaction afforded the corresponding biaryl derivatives with simultaneous reduction of nitro-to amino group and the authors attributed the reduction of the nitro group to molecular hydrogen based on literature precedent [30]. However, DMF-water mixture failed to reduce nitrobenzene to aniline at 150 °C [29]. Moreover, PdCl 2 (PPh 3 ) 2 -PCy 3 catalyzed cross-coupling of 1d with PhB(OH) 2 using 2 M K 2 CO 3 in dioxane also afforded 2a (26%), 3d (11%) and 4d (62%) in sequence. We envisioned that molecular hydrogen generated from DMF-water medium in the presence of Pd(PPh 3 ) 4 or PdCl 2 (PPh 3 ) 2 would also hydrogenolyze the azidoiodoquinolines 1 in analogy with literature observation for the selective hydrogenolysis of azidoiodoarenes by H 2 -Pd/C mixture to afford the azidoarenes [31].

3/4 4-R 4-X % Yield 2 % Yield 3 % Yield 4 a
The intriguing results observed in this investigation prompted us to propose a mechanism outlined in Scheme 2 to account for the one-pot palladium-catalyzed cross-coupling and subsequent reduction of the azido group to afford the primary 4-aminoquinolines 4. The symmetrical biaryls 2 are the result of the self-coupling of aryl groups from arylboronic acid. Homo-coupling of arylboronic acids is a side reaction usually observed for the Suzuki-Miyaura cross-coupling reactions under both Pd(PPh 3 ) 4 and Pd(OAc) 2 catalysis especially when the cross-coupling is very slow [32,33]. The self-coupling step is known to be accompanied by the release of palladium hydride (PdH 2 ) along with metaboric acid (HOB=O) liberated in the form of borate under alkaline aqueous medium used in the Suzuki-Miyaura cross-coupling reactions [32]. The intermediate palladium hydride released during the catalytic cycle may either release hydrogen or serve as hydride source to reduce oxidants present in the reaction media and generate Pd(0) [32]. Although palladium hydride is implicated in the self-coupling mechanism [32], palladium hydrides L 2 PdHCl [L = PCy 3 or P(t-Bu) 3 ], have been observed during the course of palladium-catalyzed Heck reaction [34].

Scheme 2.
Proposed mechanism for the one-pot Suzuki-Miyaura cross-coupling and reduction of 1 incorporating self-coupling of ArB(OH) 2 . The envisioned self-coupling step is presumably accompanied by a slow oxidative addition of palladium(0) complex into 1 to form A, followed by transmetallation and reductive elimination from B to afford the corresponding 2,3-diaryl-4-azidoquinoline 3 (detected by tlc or isolated by column chromatography) as invoked in the classical Suzuki-Miyaura cross-coupling reaction mechanism. We envision that intermediate 3 is reduced by palladium hydride (PdH 2 or L 2 PdHI) released from the self-coupling reaction to afford the 4-amino-2,3-diarylquinoline 4 in moderate yields. The possibility of formation of the latter via reduction of a nitrene intermediate C generated from 3 cannot be completely ruled out. Despite the fact that our proposed mechanism is necessarily speculative, it represents the best option consistent with the formation of the observed products in the presence or absence of PCy 3 .

General
Melting points were recorded on a Thermocouple digital melting point apparatus and are uncorrected. IR spectra were recorded as powders using a 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 as CDCl 3 solutions using Varian Mercury 300 MHz NMR spectrometer and the chemical shifts are quoted relative to the solvent peaks. Low-and high-resolution mass spectra were recorded at an ionization potential of 70 eV using Micromass Autospec-TOF (double focusing high resolution) instrument. The synthesis and characterization of substrates 1 have been described elsewhere [18]. A mixture of 1a (0.20 g, 0.54 mmol), phenylboronic acid (0.13 g, 1.08 mmol), 2M K 2 CO 3 (1.2 mL), PdCl 2 (PPh 3 ) 2 (0.02 g, 0.03 mmol) and PCy 3 (0.02 g, 0.05 mmol) in DMF (5 mL) in a two-necked flask equipped with a stirrer bar, rubber septum and a condenser was flushed for 30 min with argon gas. A balloon filled with argon gas was connected to the top of the condenser and the mixture was heated with stirring at 80-90 °C under argon atmosphere for 18 h and then allowed to cool to room temperature. The cooled mixture was poured into a ice-cold water and the product was taken-up into chloroform. 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 on silica gel (20% ethyl acetate-hexane) to afford 2a, 3a and 4a in sequence. A mixture of 1b (0.50 g, 1.28 mmol), phenylboronic acid (0.31 g, 2.56 mmol), PdCl 2 (PPh 3 ) 2 (0.04 g, 0.06 mmol), PCy 3 (0.04 g, 0.13 mmol), 2 M K 2 CO 3 (2.6 mL) in DMF (10 mL) was treated as described above. Work-up and column chromatography on silica gel (20% ethyl acetate-hexane) afforded 2a (19.6 mg, 10%), R F 0.90; 3b and 4b in sequence.

4-Azido-2,3-bis(4-methoxyphenyl)quinoline
A mixture of 1c (0.25 g, 0.62 mmol), phenylboronic acid (0.07 g, 1.23 mmol), Pd(OAc) 2 (0.01 g, 0.03 mmol) and 2 M K 2 CO 3 (1.2 mL) in DMF (6 mL) in a two-necked flask equipped with a stirrer bar, rubber septum and a condenser was degassed with argon for 10 min. A balloon filled with argon was connected to the top of the condenser and the mixture was heated at 80-90 °C for 6 h. The mixture was cooled to room temperature and then poured into ice-cold water. The product was taken-up into chloroform and the organic solution was washed with brine, dried (anhydrous MgSO 4 ) and then evaporated under reduced pressure. The residue was purified by column chromatography on silca gel (20% ethyl acetate-hexane) to afford three products 2a (19 mg, 21%), R F 0.94; 3c (29.8 mg, 14%), R F 0.50 and 4c (60 mg, 30%), R F 0.14 in sequence.

Conclusions
In summary, the direct one-pot palladium-mediated coupling of 2-aryl-4-azido-3-iodoquinolines 1 with arylboronic acids and subsequent reduction of the azido group by the in situ generated palladium hydride represents a convenient synthetic strategy for the construction of primary 4-amino-2,3-diarylquinolines. The isolation of the symmetrical biaryl derivatives 2 and the observed in situ reduction of the azido to amino group using either Pd(OAc) 2 , PdCl 2 (PPh 3 ) 2 or Pd(PPh 3 ) 4 as the Pd(0) catalyst sources provide further support for the involvement of palladium hydride in the reductive elimination step of the catalytic cycle leading to self-coupling of arylboronic acids [32]. At least in our opinion, the results observed in this investigation rule out the possibility of an in situ reduction of the azido group via Staudinger reaction with PPh 3 generated from the catalyst [20] or possible hydrogenation using DMF/water mixture as previously proposed in the literature [29,30]. The versatility of this methodology can be extended to develop a streamlined approach to 2,3-disubstituted primary 4-aminoquinoline libraries and their annulated quinoline derivatives. Moreover, the biaryl scaffold represents a privileged structure for pharmaceutically important compounds [36][37][38].