Direct Arylation-Based Synthesis of Carbazoles Using an Efficient Palladium Nanocatalyst under Microwave Irradiation

: Herein, an eco-friendly palladium-catalyzed tandem reaction for the one-pot synthesis of carbazoles under microwave irradiation is reported. This approach involves an amination and a direct arylation from available and inexpensive anilines and 1,2-dihaloarenes. For the development of this purpose, a novel recoverable palladium nanocatalyst supported on a green biochar under ligand-free conditions is used. Compared with other existing palladium-based protocols, the present synthetic methodology shows a drastic reduction in reaction times and excellent compatibility with different functional groups, allowing to obtain a small library of carbazoles with high yields and regioselectivity. The novel heterogeneous palladium nanocatalyst can be recycled and reused up to five times without significant loss activity.


Introduction
9H-carbazole constitutes a predominant nitrogen-containing heterocyclic compound present in both synthetic and naturally occurring alkaloids. Their planar structure is broadly distributed in natural bioactive products with significant biological properties including antibiotic, antimicrobial, anti-inflammatory, antioxidant, neuroprotector, and antitumoral [1,2]. In addition, carbazole scaffolds are useful π-extending building blocks for organic materials, such as polymeric light-emitting diodes (PLEDs) and organic lightemitting devices (OLEDs) (Figure 1) [3].
Owing to the relevance of the carbazole framework, it has emerged as an important molecular target in certain areas such as medicinal chemistry, science of materials, and industry. An extensive amount of research has been dedicated to introducing structural modifications to natural occurring carbazoles, as well as the synthesis of brand-new derivatives and finding new and efficient ways to obtain them from readily available, lowcost materials. In this context, direct-arylation of arenes is an outstanding strategy from an economic and environmental point of view in cross-coupling reactions, using stoichiometric quantities of organometallic reactants. Among the aryl halides, the most interesting would be the chlorides, owing to their low costs and wide diversity [4].
.  On the other hand, direct synthesis of carbazoles through sequential palladium catalysed cross-coupling C-N/C-C bond formation has emerged as an attractive synthetic approach in the last decade.
In 2009, Ohno and co-workers reported an interesting N-arylation and oxidative biaryl coupling for the carbazole synthesis from anilines and aryl triflates under homogenous palladium (II) acetate as catalyst [6].
In 2016, Woo and co-workers reported the one-pot synthesis of carbazoles via Suzuki cross-coupling and consecutive reductive Cadogan cyclization employing ortho-halonitroarenes and arylboronic acids as starting materials [7]. Despite these considerable advances, they require complex precursors, drastic reaction conditions, expensive non-recoverable catalysts, and the presence of phosphine ligands and/or additives.
These drawbacks could be addressed by heterogeneous nanocatalysis based on transition metals, which represent enormous progress in both industry and academic areas, owing to their advantages related to atomic economy, low toxicity, atomic efficiency, and eco-friendliness [8].
In this context, microwave-assisted organic synthesis (MAOS) denotes a mighty and useful tool in heterocyclic chemistry that allows to reduce reaction time and the generation of by-products, leading to an improvement in the overall yields. Therefore, the combination of MAOS and heterogeneous catalysis represents an attractive eco-friendly approach for the synthesis of functionalized carbazoles [9].
Ackerman and co-workers reported an elegant palladium-catalyzed N-arylation and C-H activation, leading to the synthesis of carbazoles from easily attainable anilines and 1,2-dihaloarenes [10]. The cited protocol is limited because of the need for activated anilines, long reaction times, the presence of phosphine as a ligand, and unrecoverable palladium catalysts.
Inspired by these results, we herein propose an alternative, efficient, and straightforward palladium-catalyzed intermolecular C-N bond formation and intramolecular C-H arylation between anilines and 1,2-dihaloarenes, which allows access to carbazole derivatives through a one-pot process. For this purpose, a novel palladium heterogeneous catalyst and microwave irradiation were employed. The nanoparticles of palladium are supported on biochar (henceforth referred to as PdNPs/BC)-the solid residue of the pyrolysis of sunflower seed hulls, a plentiful and regional agricultural waste.
Moreover, through the application of microwave irradiation, the severe reaction conditions used by other known protocols have been improved and reaction times have been shortened from up to 18 h to barely 25 min.

Results and Discussion
We began our investigations using aniline 1a and 1,2-dichlorobenzene 2a as starting materials in the presence of a set of palladium-based catalysts, both homogeneous and heterogeneous (Table 1). For this purpose, the reaction conditions proposed by Ackermann were used as a starting point {[Pd] (5 mol%), N,N-dimethylpyrrolidine (NMP), K3PO4, 130 °C, 18 h} (Table 1). During control experiments, the tested homogeneous catalysts showed low activity and efficiency in the generation of our desired product. To improve these results, we made use of a powerful and versatile tool to decrease reaction times and limit the generation of by-products; that is, microwave-assisted organic synthesis. No reaction progress was detected when the reaction was performed without catalyst (entry 1). To our satisfaction, the corresponding carbazole 3 was obtained in 19% yield when our novel PdNPs/BC was used under microwave irradiation (entry 7). In contrast, the thermal conditions at both 130 °C and 180 °C for 18 h led to carbazole in low yields (entries 7 and 10). An improvement of the yield (43%) was accomplished when the reaction was subjected at 200 W and 180 °C for 25 min. Among the commercial homogeneous catalysts tested, PdCl2(PPh3)2 and PdCl2(MeCN)2 led to 3 in low yields (entry 2 and 3), whereas Pd(PPh3)4 and Pd2(dba)3 showed less or no activity (entry 2 and 4). By increasing the temperature using the homogeneous PdCl2(MeCN)2, no reaction progress was detected (entry 6). Additionally, other nanopalladium heterogeneous catalysts were tested. PdNPs/Al2O3 led to 3 in low yields in both thermal and microwave conditions at 130 °C and 180 °C, whereas PdNPs/PbO were inactive in the same reaction conditions (entries 8 and 9).
The low reactivity of both PdNPs supported on Al2O3 and PbO, respectively, by comparison with PdNPs/BC strongly suggests that BC is not an innocent support for the reaction. The reason for BC promoting Pd catalytic features would be related the peculiar surface chemistry of BC, which is a highly functionalized material. Unveiling the exact nature of BC surface and its role in reaction is beyond the scope of the present study, and will be discussed in future studies of our group.
PdNPs/BC 130 11 19 8 PdNPs/PbO 130 --trace 9 PdNPs/Al2O3 130 trace 9 10 PdNPs/BC 180 18 43 11 PdNPs/Al2O3 180 10 12 Standard reaction conditions: Subsequently, various reaction conditions such as solvents, bases, and PdNPs/BC loading were evaluated (Table 2). Upon decreasing the catalyst load to 2.5 mol%, a low yield of 3 (16%) was obtained (entry 1). Surprisingly, when the reaction was carried out using 15 mol% of the PdNPs/BC, the carbazole was obtained in 76% yield (entry 3). A moderate yield (57%) of carbazole was obtained when an intermediate load of catalyst (10 mol%) was used (entry 2). Next, several polar solvents with elevated boiling points were evaluated. Among the solvents tested, dimethyl sulfoxide (DMSO) at 180 °C demonstrated the best efficiency (entry 6), whereas N,N-dimethylformamide (DMF) and N,Ndimethylacetamide (DMAc) showed no significant changes in comparison with N-Methyl-2-pyrrolidone (NMP) (entries 4 and 5). Finally, different bases were examined. The inorganic base KOAc showed the best performance (entry 9), whereas different carbonates and organic bases such as NaOt-Bu did not improve yields (entries 8-11). Additionally, the effect sof irradiation time and power were also evaluated. When the reaction was subjected to 200 W for 25 min, a complete conversion of starting materials was observed, whereas prolonged times led to an increase in the formation of by-products. Performing the reaction at 100 W led to no reaction progress both at reaction times of 25 and 60 min. Irradiation power at 300 W for more than 25 min led to the carbazole in a lower yield. Therefore, the use of irradiation power at 200 W for 25 min was determined as the optimal condition.
Under the optimized reaction conditions ( Table 2, entry 9), we carried out the scope and limitations to our methodology by employing different 1,2-dihaloarenes and aniline (1a) ( Table 3). When the reaction was carried out using 1,2-dibromobenzene (2c), carbazole 3 was obtained in an excellent yield (90%). Besides, using 1-bromo-2-chlorobenzene (2c) as substrate, the desired product 3 was obtained in 81% yield. As shown in Table 3, the formation of carbazole was not limited while resorting to 1,2-dihaloarenes bearing good leaving groups, such as bromine. In this context, it is important to note that the present methodology enables to obtain carbazole using inexpensive aryl chlorides as electrophilic reagent. In addition, neither formation of homocoupling by-products nor significant differences in term of yields were observed using aryl chlorides instead of aryl bromides. Having established the reaction conditions, we studied the scope of the reaction using several anilines and 1,2-dihaloarenes bearing electron-donating and electron-withdrawing groups. As shown in Table 4, the present protocol is compatible with a variety of functional groups, including fluorine, nitro, methoxy, alkyl, and methyl ketones. The presence of moderate or stronger electron-donating groups in position 4, such as methyl or methoxy in aniline, afforded products 4 and 6 in excellent yields. In addition, the scope with anilines bearing electron-withdrawing groups, such as fluorine, nitrile, or methyl ketone groups, led to products 5, 8, and 9 in excellent yields (68-75%). Table 4. Substrate scope for the direct synthesis of functionalized 9H-carbazoles [a] . Moreover, the chemo-and regioselectivity of the process was evaluated using asymmetrical anilines. When the reaction was carried out using 3-methylaniline and 1,2-dichlorobenzene, products 7 and 7a were detected in the isomeric ratio of 1:1 by 1 H NMR, which denotes a low control of the regioselectivity. However, an excellent regioselectivity of product 7 was observed using 1-bromo-2-chlorobenzene (2c) as ortho-dihalobenzene. Considering the regioselectivity observed, we studied the scope using anilines bearing strong electron-withdrawing groups such as 3-nitroaniline. To our satisfaction, using 3-nitroaniline and 2c, product 10 was obtained in good yield (61%). The 1,2-dichlorobenzenes bearing moderate or strong electron-withdrawing groups in position 4 led to products 12 and 13 with an excellent yield and regioselectivity. Additionally, this protocol enabled access to the α-carboline 11 in excellent yields from 2-aminopyridine and 1-bromo-2-chlorobenzene (2c) as starting materials.

Reagent and conditions:
Finally, the recyclability of the PdNPs/BC catalyst was studied using the direct synthesis of carbazole 3 as the reaction model. After completion of the reaction (monitored by TLC), the nanocatalyst was easily separated from the reaction mixture by filtration and washed several times with EtOAc, and then dried under vacuum to be used directly for further catalytic reactions. As shown in Figure 3, no significant loss of catalytic efficiency was observed up to five cycles.

Conclusions
In conclusion, we have developed a practical, eco-friendly, and selective methodology for the synthesis of carbazoles promoted by a catalytic system based on PdNPs supported on green biochar. The novel catalyst could be recycled up to at least five times without significant loss activity. Additionally, the present methodology enabled us to access a variety of carbazoles using inexpensive aryl chlorides as electrophiles and anilines as starting materials. Moreover, the prolonged reaction times were drastically reduced to minutes using microwave irradiation. Furthermore, the present protocol is compatible with different functional groups and does not require the presence of ligands or additives as the traditional methods reported up to date.

General Information
Unless otherwise noted, reagents were obtained commercially and used without further purification. Solvents were dried and distilled in accordance with standard procedure (ref). Reactions were monitored by thin-layer chromatography on silica gel plates (60F-254) visualized under UV light and/or using 5% phosphomolybdic acid in ethanol. All 1 H and 13 C NMR spectra were recorded at room temperature in CDCl3 or DMSO-d6 on a Bruker Avance ARX-300 spectrophotometer. Chemical shifts (δ) are reported in parts per million (ppm) from tetramethylsilane (TMS) using the residual solvent resonance (CDCl3: 7.26 ppm for 1 H NMR, 77.16 ppm for 13 C NMR. Multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet; brs = broad signal). IR spectra were recorded on a Perkin-Elmer Paragon 1000 FT-IR spectrometer in the ATR mode at room temp. Melting points were determined using a Büchi 510 apparatus and are not corrected. Mass spectra (EI) were obtained at 70 eV on a Hewlett Packard HP-5890 GC-MS instrument equipped with a HP-5972 selective mass detector. The purity of volatile compounds and the chromatographic analyses (GC) was determined with a GC Shimadzu (GC-14B) with a flame ionization detector equipped with a HP-5MS column (30 m × 0.25 mm × 0.25 μm) using nitrogen as carrier gas. High resolution mass spectra were recorded on Thermo Fisher LTQ Orbitrap XL (for EI) and a Finnigen MAT 95 (for ESI). Flash column chromatography was performed using Macherey Nagel MN silica gel 60M (0.040-0.063 mm/230-240 mesh ASTM). Microwave reactions were performed using microwave oven CEM Discover in sealed reaction vessels. The palladium loading of the catalyst was determined by atomic absorption spectrometry (AAS) using Perkin Elmer AAnalyst 700 equipment. Powder X-ray diffraction (XRD) patterns were recorded on a Philips PW1710 BASED Diffractometer, operating at 45 kV and 30 mA, fitted with a graphite monochromator getting Cu Ka 1 radiation (ʎ ¼ 0.15406 nm). The samples were characterized by transmission electron microscopy (TEM), employing Joel 100 CX2 (Tokyo, Japan) apparatus. Approximately one hundred palladium particles were measured to perform the particle size distribution in order to obtain the mean particle size (d) [11]. Nitrogen adsorption/desorption isotherm at 77 K was obtained with a Nova 1200e Quantachrome Instrument. The specific surface areas were measured following the Brunauer-Emmett-Teller (BET) method.

Microwave Reactions
All microwave reactions were carried out following the same procedure. Anilines (1.2 mmol), 1,2-dihaloarenes (1 mmol), KOAc (3 mmol), PdNPs/BC (15 mol%), and dry DMSO (5 mL) were added to a vessel tube with a magnetic stirring bar. The resulting mixture was heated at 180 °C under microwave irradiation (200 W) for 25 min. The progress of the reaction was monitored by TLC and GC-MS. The crude product was treated with EtOAc. The catalyst was recovered by filtration and washed several times with the same solvent. The filtrate was washed twice with a brine and then dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the desired carbazole was purified by column chromatography using silica gel 60 as adsorbent.
The specific surface area of the PdNPs/BC, as measured by BET methodology, was 65m 2 /g.

Funding:
This research was funded by the National Council of Scientific and Technical Research (Consejo Nacional de Investigaciones Científicas y Técnicas; CONICET), the National Agency for Scientific and Technological Promotion (Agencia Nacional de Promoción Científica y Tecnológica; ANPCyT), and the Universidad Nacional del Sur (Secretaría General de Ciencia y Tecnología, Universidad Nacional del Sur; SGCyT-UNS), Argentina.