Design and Exploration of Catalytic Activity of Two-Dimensional Surface-Engineered Graphene Oxide Nanosheets in the Transannulation of N-Heterocyclic Aldehydes or Ketones with Alkylamines.

In this work, pharmaceutically and biologically important compounds containing imidazo[1,5-a]pyridine nuclei have been synthesized via transannulation of N-heteroaryl aldehydes or ketones with alkylamines using a graphene oxide-supported copper catalyst. The nanocatalyst was fabricated by the covalent immobilization of 4-aminoantipyrine onto an amine-functionalized graphene oxide nanosupport followed by its metallation with copper acetate. Structural analysis by transmission electron microscopy, scanning electron microscopy, X-ray photoelectron spectroscopy (XPS), and X-ray diffraction demonstrates that the two-dimensional sheet-like structure of graphene oxide is maintained even after the chemical modifications, whereas XPS revealed crucial information related to elemental composition and surface electronic states of the metal present in the catalyst. Apart from this, Fourier transform infrared spectroscopy helped in identifying the degree of oxidation and the presence of oxygenated groups in graphene oxide nanocomposites. As a heterogeneous catalyst, this graphene oxide-supported copper complex showed moderate to good catalytic activity in the C(sp3)-H bond activation/amination of a variety of substrates. This superior catalytic performance originated from the unique 2-dimensional structure of graphene oxide-based material which provided space between graphitic overlayers due to appropriate positioning of metal on their basal planes, decreasing the diffusion resistances of reactant surfaces, thus making it function as a nanoreactor. More importantly, this nanomaterial could be recovered easily and reused repeatedly by simple washing without chemical treatment with no appreciable loss in its catalytic activity, showing good potential for increasing the overall turnover number of this synthetically useful catalyst.

Introduction

Transition-<span class="Chemical">metal-catalyzed C–H amination represents an attractive strategy for the synthesis of <span class="Chemical">nitrogen-containing heterocyclic compounds as it provides undeniable benefits of high atom economy and reduced waste generation, which cause such reactions to fall under the banner of green chemistry.[1−3] Although a noteworthy advancement in the C(sp2)–H bond activation strategy enabling C(sp2)–N bond formation has been witnessed in recent years,[4−7] yet the catalytic functionalization of the relatively inert C(sp3)–H bonds which can provide a unique access to site-selective C–N bonds remains a major challenge in synthetic organic chemistry.[8−13] To accomplish C(sp3)–H bond activation, various amine sources have been scrutinized which include arylamines and aliphatic amines, amides, azides, haloamines, and so forth in the presence of suitable transition-metal catalysts. Recently, N-heteroarenes have proven their efficacy as an excellent amino source for the metal-catalyzed C(sp3)–H amination.[14−17]

<span class="Chemical">Imidazo[1,5-a]pyridine scaffolds are a class of <span class="Chemical">nitrogen-bridgehead-fused heterocycles, present in several pharmacologically important mole<span class="Chemical">cules that unveil a broad spectrum of biological activities such as antimicrobial, antineoplastic, antianxiety, anti-inflammatory, and so forth.[18−21] Apart from comprising intrinsic exceptional biological and pharmacological properties, these compounds also serve as expedient predecessors for a variety of functional group transformations. To date, a paucity of approaches have been reported to construct imidazo[1,5-a]pyridines fundamentally relying on the Vilsmeier-type protocol and Wallach imidazole synthesis.[22−24] Nevertheless, none of the methodologies enlisted in the literature are environmentally benign because they inevitably involve the use of either excess amount of additives, active starting materials, or multistep processes.[25−30] Therefore, the development of new flexible, atom-economic, and proficient protocols for these imidazo[1,5-a]pyridines is of upsurge interest. In this direction, copper-catalyzed direct transannulation of N-heteroaryl aldehydes or ketones with alkylamines that involves a oxidative C(sp3)–H activation strategy has attracted the synthetic pursuit of research studies as it represents one of the most powerful gateways to obtain a diverse range of the substituted imidazo[1,5-a]pyridines simply through one-pot condensation–amination–oxidative dehydrogenation process.[31−35] Though the homogeneous copper catalysts offer high conversion percentage, selectivity, and yields under relatively mild operating conditions, but their industrial applicability is hampered by the inherent problem of catalyst separation from the reaction mixture and its recyclability. Moreover, the presence of copper residues in the product stream renders its commercial utility rather desolate in the pharmaceutical industries. In view of these severe limitations, there is an urgent need to develop novel retrievable catalytic systems that can surmount the challenges of homogeneous catalysis and also preserve the best attributes of both homogeneous and heterogeneous catalysts for the generation of a library of imidazo[1,5-a]pyridine nuclei.

The introduction of novel nanotechnologies has empowered the generation of solid-supported heterogeneous nanoscale catalysts, which are ef<span class="Chemical">fen>ctive tools for controlling chemical reactivity as well as facile recovery.[36−43] Amongst a multitude of solid nanostructures enlisted in the literature, two-dimensional (<span class="Chemical">2D) <span class="Chemical">graphene oxide in particular offers excellent prospects to provide a platform for such third-generation catalytic systems owing to their exceptional structural properties such as nanometer size, excellent chemical and thermal stability, good accessibility, porosity, and large surface area-to-volume ratio. In addition, these nanosheets provide the opportunity to tune the structure of the catalyst via chemical modifications because of the presence of numerous hydroxyl, epoxy, carboxyl, and carbonyl groups on its surface which allow the immobilization of a diverse array of reagents and also intensify their use in different chemical transformations.[44−48]

Our recent fast-growing research fo<span class="Chemical">cun>sed on the development of sustainable organic–inorganic hybrid nanomaterials motivated us to come up with new <span class="Chemical">graphene oxide-based retrievable <span class="Chemical">2D nanocatalytic system that substantiated their efficiency in C(sp3)–H activation for direct transannulation of N-heteroaryl aldehydes or ketones with alkylamines using molecular oxygen as an oxidant.[49−54] This novel nanostructured catalyst not only demonstrates benefits such as the ease of product separation but can also be used for multiple runs without any appreciable loss in its catalytic activity. The reason behind the good catalytic efficacy can be attributed to chemically modified graphene oxide that forms crumpled nanosheets/nanostacks which provide engineered internal cavities creating unique incarcerate nanoscale environments for chemical reactions. Moreover, utilization of molecular oxygen as an environmentally benign oxidant to achieve this oxidative transformation functions as a prevailing tool to enhance the sustainability of chemical process as there is no formation of side product. To the best of our knowledge, this report is the first example of atom economical and environmentally benign C–H amination wherein a graphene oxide-based copper catalyst has been effectively exploited for the synthesis of pharmaceutically and biologically significant compounds.

Experimental Section

Materials and Reagents

<span class="Chemical">Graphite flakes (Sigma-Aldrich), <span class="Chemical">3-aminopropyltriethoxysilane (<span class="Chemical">APTES, Alfa Aesar), and 4-aminoantipyrine (AA) (Spectrochem Pvt. Ltd, India) were commercially procured. All other reagents and solvents employed for the synthesis were of analytical grade and used as received.

Characterization Techniques

Transmission electron microscopy (TEM) analyn class="Chemical">sis was carried using a Tecnai G2 T30 microscope in order to determine the morphology of nanosheets. Field emission scanning electron microscopy (FESEM) images were obtained in order to derive information about the morphological characteristics of nanosheets using a Tescan Mira 3 FESEM instrument. Energy-dispersive X-ray spectroscopic (EDS) analysis equipped with the FESEM (Zeiss FESEM) was achieved for the elemental mapping of the nanocomposites. Fourier transform infrared (FT-IR) spectra were acquired through a PerkinElmer Spectrum 2000 using the KBr pellet method that was operative in the range of 4000–500 cm–1 under atmospheric conditions with a resolution of 1 cm–1. Powder X-ray diffraction (XRD) was carried out using a Rigaku Ultima (IV) diffractometer with Cu Kα radiation at a scanning rate of 2° min–1 in the 2θ range of 8–80° (40 kV, 40 mA). Energy-dispersive X-ray fluorescence (ED-XRF) spectroscopy was performed using a Fischerscope X-ray XAN-FAD BC. The copper content in the nanocatalyst was estimated by using a flame atomic absorption spectrometer (model no. N3180021 PinAAcle 500) using an acetylene flame. All of the derived products were examined through the gas chromatography–mass spectrometry (GC–MS) hyphenated technique that was conducted utilizing the Agilent gas chromatograph (6850 GC) with a HP-5MS 5% phenyl methyl siloxane capillary column (30.0 m × 250 μm × 0.25 μm) and a quadrupole mass filter equipped 5975 mass selective detector using helium as the carrier gas.

Preparation of Organoamine-Functionalized Graphene Oxide Nanocomposites (APTES@GO)

GO was prepared by the oxidation of <span class="Chemical">graphite powder via the modified Hummers’ method.[55] For obtaining <span class="Chemical">amine-functionalized <span class="Chemical">graphene oxide (APTES@GO) nanocomposites, APTES (2 mmol) was added dropwise to a well-dispersed solution of GO (1.0 g) in ethanol (200 mL) and stirred under reflux conditions for 5 h.[56] The resulting mixture was separated via centrifugation, washed several times with ethanol to remove residual APTES, and dried under vacuum overnight.

Synthesis of Graphene Oxide Nanosheet-Based Copper Catalyst (Cu@AA@APTES@GO)

The final synthesis of the <span class="Chemical">Cu@AA@<span class="Chemical">APTES@GO nanocatalyst was carried out using a two-step procedure. First, organoamine-functionalized graphene oxide (0.5 g) was dispersed in ethanol (30 mL) using an ultrasonic bath. Thereafter, AA was added to suspension and stirred under reflux conditions for 6 h in order to obtain AA@APTES@GO.[57] In the next step, AA@APTES@GO was added to a solution containing copper acetate (1.5 mmol) in acetone (100 mL) and stirred at room temperature for 24 h. The resulting nanocomposites were removed through centrifugation, washed thoroughly with ethanol, and dried under vacuum to obtain the Cu@AA@APTES@GO nanocatalyst (Scheme ).[58,59]

Scheme 1

Schematic Illustration for the Synthesis of Cu@AA@APTES@GO Nanocatalyst

General Procedure for the Reaction

A mixture of <span class="Chemical">2-acetylpyridine (0.10 mmol) and <span class="Chemical">benzyl amine (0.10 mmol) was refluxed at 80 °C in the presence of the <span class="Chemical">Cu@AA@APTES@GO nanocatalyst (15 mg) using acetonitrile (2 mL) as a solvent and then stirred for the desired reaction time. The progress of the reaction was monitored by thin-layer chromatography (ethyl acetate–hexane). After completion of reaction, the mixture was allowed to cool to room temperature and the nanocatalyst was recovered via centrifugation. Then, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were separated and dried over Na2SO4, and the solvent was removed under vacuum. The products obtained were thereafter analyzed and confirmed by GC–MS.

Results and Discussion

Motivation and Strategy

Considering the scarcity of sustainable methods integrating efficiency, selectivity, and reusability in a n class="Chemical">single platform, through the present work, we report graphene oxide-supported copper catalyst for the synthesis of imidazo[1,5-a]pyridines. The utilization of the 2D heterostructure of the catalytic material that provides intriguing confined space between graphitic overlayers and metal surfaces enables it to function as a nanoreactor, thereby playing an indispensable role in expediting this reaction and affording the target products with good to excellent yield. Also, the extremely high thermal conductivity of graphene oxide allows conduction and diffusion of the heat produced during catalytic reactions that makes it a good candidate for the support matrix.

FT-IR Spectroscopy

The FT-IR spectra of GO, <span class="Chemical">APTES@GO, AA@<span class="Chemical">APTES@GO, and Cu@AA@APTES@GO are demonstrated in Figure . FT-IR spectroscopy identifies the degree of oxidation and presence of the oxygenated species in GO. In the spectrum of GO, the characteristic peaks at 3410, 1730, 1624, 1402, and 1062 cm–1 are due to the OH, C=O in −COOH, aromatic C=C, carboxy C–O, and epoxy C–O stretches, respectively, situated at the edges of GO nanosheets.[60] Thereafter, the covalent functionalization of the nanosupport with APTES is confirmed through the presence of additional absorption band at 2930 cm–1 which is assigned to stretching vibrations of C–H bonds, whereas the bands at 1622 and 3434 cm–1 that can be attributed to N–H stretching and bending vibrations. The sequential introduction of ligand (AA) to the silane terminal by condensation with apical amine groups is verified by the appearance of a strong band at 1630 cm–1 which is associated with the stretching vibrations of C=N. Consistent with this interpretation, a noticeable shift (1626 cm–1) in the imine vibrations of the Schiff base which can be accredited to electron delocalization of C=N and coordination interaction with the copper metal.[61] These results confirm the successful anchoring of copper complex onto the GO surface as Cu@AA@APTES@GO.

Figure 1

FT-IR spectra of (a) GO, (b) APTES@GO, (c) AA@APTES@GO, and (d) Cu@AA@APTES@GO.

FT-IR spectra of (a) GO, (b) <span class="Chemical">APTES@GO, (c) AA@<span class="Chemical">APTES@GO, and (d) Cu@AA@APTES@GO.

XRD Analysis

XRD analysis was done in order to investigate the phase structure and crystallinity of the nanocompon class="Chemical">sites. Figure depicts that graphite powder exhibits a high degree of crystallinity with an intense and sharp diffraction peak at 2θ = 26.8° which correspn>onds to the crystal plane (002) with an interplanar distance of 0.33 nm.[62] In contrast, unmodified GO shows a lower degree of crystallinity with a small broad diffraction peak at 2θ = 10.7° having d-spn>acing 0.825 nm corresponding to the (001) crystal plane.[63] Clearly, the increase in the interlayer distance of graphene oxide indicates the hydration and exfoliation of GO in an aqueous medium which revealed the formation of various oxygen containing functionalities such as <span class="Chemical">hydroxyl, epoxy, carbonyl, carboxyl groups, and so forth. After the immobilization of aminopropyl moiety on GO nanosheets, the diffraction peak at around 10.7° does not disappear, suggesting that the structure of GO is not destroyed; however, a decrease in the intensity of this peak can be observed along with the appearance of a new peak around 22°.[64] Moreover, ligand-grafted amine-functionalized graphene oxide and final nanocatalyst showed further decrease in the intensity of both of these diffraction peaks. The decrease in the intensity of the diffraction peak of GO with successive surface modifications could be attributed to the intercalation of functional groups, suggesting the decrease in ordered arrangement of GO nanosheets.[65−67]

Figure 2

Powder XRD of (a) graphite, (b) GO, (c) APTES@GO, (d) AA@APTES@GO, and (e) Cu@AA@APTES@GO.

Powder XRD of (a) <span class="Chemical">graphite, (b) GO, (c) <span class="Chemical">APTES@GO, (d) AA@<span class="Chemical">APTES@GO, and (e) Cu@AA@APTES@GO.

Morphology Analysis

<span class="Chemical">FESEM and TEM are powerful magnification tools which provide detailed information about the evolution of morphology, composition, and texture of nanocomposites. The nanomaterials, both before and after grafting, were also characterized by <span class="Chemical">FESEM and TEM. As displayed in Figure , it can be visualized that GO inherits twisted <span class="Chemical">2D planar morphology. Further, as we move from GO to APTES@GO to Cu@AA@APTES@GO, the extent of crumpling and protrusions increases which provide evidences for enormous surface area of nanomaterials. Therefore, these lamellar folded flakes (well-stacked layered structure) with wrinkles induce not only high degree of active catalytic sites but also serve as a versatile platform for efficient chemical transformations. Besides, a thorough analysis of TEM micrograph of GO confirms the corrugated sheet-like nature of material with a lateral dimension up to several micrometers. Further, it is observed that even after the surface modification with organic functionalization moieties, the corrugated sheet-like structure of GO nanocomposites is maintained. Apart from this, the selected-area electron diffraction pattern of GO shown in the inset of Figure f shows sharp diffraction spots indicating amorphous nature of GO flakes.[68−70] Additionally, SEM and TEM images of the recovered nanocatalyst do not show any change in their crumpled morphology, suggesting that the catalyst is robust enough to withstand the applied reaction conditions (Figures S1 and S2).

Figure 3

FESEM micrographs of (a) GO, (b) APTES@GO, and (c) Cu@AA@APTES@GO and TEM micrographs of (d) GO, (e) APTES@GO, and (f) Cu@AA@APTES@GO.

<span class="Chemical">FESEM micrographs of (a) GO, (b) <span class="Chemical">APTES@GO, and (c) <span class="Chemical">Cu@AA@APTES@GO and TEM micrographs of (d) GO, (e) APTES@GO, and (f) Cu@AA@APTES@GO.

X-ray Photoelectron Spectroscopy

X-ray photoelectron spectra of <span class="Chemical">Cu@AA@<span class="Chemical">APTES@GO are presented in Figure . The surface electronic states and the interactions of chemically modified GO were assessed by X-ray photoelectron spectroscopy (XPS). The appearance of a band around 286.2 eV designates C–O–C and C–OH bonds which indicate a considerable degree of oxidation and the presence of different oxygen-containing groups. In addition, the C 1s spectrum of the catalyst reveals two more bands at 284.7 that correspond to C–H and C–C bonds and 288.4 eV which arises from O–C=O bonds. Besides, new bands at 399.4, 400.8, and 401.33 emerging in the N 1s spectrum are attributed to C–N=C, C–N–H, and =N–, respectively (Figure S3). Moreover, the presence of a band at 102.1 eV accredited to Si–O arises in the Si 2p spectrum. This designates the silylation reaction between silanol group of APTES and GO surface hydroxyl groups. Further, the Cu 2p XPS spectrum of the nanocatalyst shows two typical bands at 934.6 and 954.5 eV, which correspond to the binding energies of copper(II). In addition, a Cu 2p3/2 satellite peak appearing at 943.5 eV explained the coordination interaction between the ligand and the copper center.[71,72]

Figure 4

Full-range XPS spectra of (a) Cu@AA@APTES@GO and core-level spectra of (b) C 1s, (c) N 1s, (d) O 1s, (e) Si 2p, and (f) Cu 2p spectra of the nanocatalyst.

Full-range XPS spectra of (a) <span class="Chemical">Cu@AA@<span class="Chemical">APTES@GO and core-level spectra of (b) C 1s, (c) N 1s, (d) O 1s, (e) Si 2p, and (f) Cu 2p spectra of the nanocatalyst.

Elemental and Compositional Analysis

The composition of nanostructured GO-supported catalyst was also confirmed by EDS (Figures , 6, and S4) and ED-XRF n class="Chemical">spectroscopy (Figure S5). EDS elemental mapping images of the graphene oxide-supported copper catalyst clearly show the presence of all of the elements, that is, Cu, C, N, Si, and O on the surface of the GO nanosheets which provides the evidence for the successful organoamine functionalization, ligand grafting, and metallation. Further, a well-resolved peak of copper in the ED-XRF spectrum of Cu@AA@APTES@GO also confirms the successful metallation of AA@APTES@GO.[73] Subsequently, the quantitative estimation of the copper content in the synthesized nanocatalyst was done after digestion using atomic absorption spectroscopy, and the corresponding copper loading was estimated to be 0.126 mmol g–1.

Figure 5

(a) FESEM image Cu@AA@APTES@GO of the catalyst and corresponding elemental mapping images of (b) carbon, (c) nitrogen, (d) oxygen, (e) silicon, and (f) copper.

Figure 6

EDS spectra of the Cu@AA@APTES@GO catalyst.

(a) <span class="Chemical">FESEM image <span class="Chemical">Cu@AA@<span class="Chemical">APTES@GO of the catalyst and corresponding elemental mapping images of (b) carbon, (c) nitrogen, (d) oxygen, (e) silicon, and (f) copper.

EDS spectra of the <span class="Chemical">Cu@AA@<span class="Chemical">APTES@GO catalyst.

Raman Spectroscopy

Raman spectroscopy is a powerful technique to study the structural and chemical changes in the obtained nanomaterials. The Raman n class="Chemical">spectra of GO, APTES@GO, AA@APTES@GO, and Cu@AA@APTES@GO are shown in Figure . The presence of two characteristic peaks centered at 1597 and 1347 cm–1 is attributed to G and D bands of GO which are associated with the vibrations of sp2 bonded carbon networks.[74,75] Further, chemical modifications of GO are confirmed by comparing the intensity ratio of D and G bands (ID/IG). The increase in the ID/IG ratio from 0.98 to 1.01, 1.04, and 1.05 confirms the stepwise covalent anchoring of aminosilane chain, ligand grafting, and metallation onto the surface of GO.[76]

Figure 7

Raman spectra of GO (black), APTES@GO (red), AA@APTES@GO (green), and Cu@AA@APTES@GO (blue).

Raman spectra of GO (black), <span class="Chemical">APTES@GO (red), AA@<span class="Chemical">APTES@GO (green), and Cu@AA@APTES@GO (blue).

Optimizations

Initial optimization studies for transannulation of <span class="Chemical">N-heteroaryl aldehydes or <span class="Chemical">ketones were carried out using 2-acetylpyridine and benzyl amine as standard substrates. The presence of the catalyst was found to be necessary because no appreciable amount of the product was detected in its absence. Thereafter, we employed different catalysts for affording the desired product (Table S1). The highest conversion percentage was obtained in the case of the Cu@AA@APTES@GO nanocatalyst, suggesting the efficiency of the graphene oxide-based copper nanocomposites for C(sp3)–H amination (Figure S8).

Amount of the Catalyst

The key parameter to evaluate the catalytic performance is the ef<span class="Chemical">fect of the amount of the catalyst. In order to evaluate its ef<span class="Chemical">fect on model reaction, we carried out six experiments in which we simply increased the amount of the catalyst from 5 to 30 mg. It was observed that the 100% conversion was obtained when the amount of the <span class="Chemical">Cu@AA@APTES@GO nanocatalyst was increased from 5 to 15 mg (Figure ). Further, it was observed that the conversion percentage remained same on increasing the amount of the catalyst up to 25 mg. However, on increasing the amount of the catalyst to 30 mg, conversion percentage decreased because of the low dispersity of the excess catalyst in the reaction media which is caused due to steric hindrance of the mass transfer between the active site and reagent. Therefore, the best result was obtained when the reaction was performed using 15 mg of the nanocatalyst.

Figure 8

Effect of amount of the catalyst on the transannulation of N-heteroaryl aldehydes or ketones [reaction conditions: 2-acetylpyridine (0.10 mmol), benzyl amine (0.10 mmol), acetonitrile (2 mL), catalyst (x mg), 10 h, 80 °C].

Ef<span class="Chemical">fect of amount of the catalyst on the transannulation of N-heteroaryl <span class="Chemical">aldehydes or <span class="Chemical">ketones [reaction conditions: 2-acetylpyridine (0.10 mmol), benzyl amine (0.10 mmol), acetonitrile (2 mL), catalyst (x mg), 10 h, 80 °C].

Effect of Time

The catalytic efficacy of <span class="Chemical">Cu@AA@<span class="Chemical">APTES@GO in the transannulation of <span class="Disease">N-heterocyclic aldehydes was studied at different time intervals. The conversion percentage has been represented as a function of time in Figure . A close comparison of results revealed that the conversion percentage increased from 25 to 100% as time was increased from 2 to 10 h. Further, when the reaction was continued for 12 h, no significant change was observed. Therefore, the reaction time for transannulation of N-heteroaryl aldehydes or ketones was optimized as 10 h.

Figure 9

Effect of time on the transannulation of N-heteroaryl aldehydes or ketones [reaction conditions: 2-acetylpyridine (0.10 mmol), benzyl amine (0.10 mmol), acetonitrile (2 mL), catalyst (15 mg), 80 °C].

Ef<span class="Chemical">fect of time on the transannulation of <span class="Chemical">N-heteroaryl aldehydes or <span class="Chemical">ketones [reaction conditions: 2-acetylpyridine (0.10 mmol), benzyl amine (0.10 mmol), acetonitrile (2 mL), catalyst (15 mg), 80 °C].

Effect of Temperature

Temperature is one of the significant parameters which play a vital role in influencing the thermodynamic activities of the reaction. In order to determine the most favorable reaction conditions un class="Chemical">sing Cu@AA@APTES@GO as a catalyst, the test reaction was carried out at diverse range of temperatures (40–80 °C). The conversion percentage has been represented as a function of temperature (Supporting Information Figure S6). Compared with the results obtained at 80 °C, a lower conversion of 35% to the desired product was obtained at 60 °C, suggesting that the catalytic activity of the graphene oxide-based copper nanocatalyst decreased by decreasing the reaction temperature. As expected, no desired product was formed at room temperature. Notably, the optimized temperature for the synthesis of imidazo[1,5-a]pyridines was 80 °C.

Effect of Solvents

Nature of solvents has a remarkable impact on convern class="Chemical">sion percentage of the desired products. Therefore, in order to study their effect on the concerned reaction, test substrates were subjected to different polar and nonpolar solvents. First, the test reaction was carried out in polar solvents (ethanol and acetonitrile) which resulted in 73 and 100% of desired product, whereas in the presence of nonpolar solvents (hexane and toluene), only 57 and 63% of conversion percentage were obtained (Figure ). In fact, lowest conversion percentage was observed when the experiment was run in solvent-free conditions, even if the reaction was carried out for a prolonged period of time. Therefore, the order of reactivity in different solvents was found to be acetonitrile > ethanol > toluene > hexane > solvent-free.

Figure 10

Effect of solvents on the transannulation of N-heteroaryl aldehydes or ketones [reaction conditions: 2-acetylpyridine (0.10 mmol), benzyl amine (0.10 mmol), solvent (2 mL), catalyst (15 mg), 10 h, 80 °C].

Ef<span class="Chemical">fect of solvents on the transannulation of <span class="Chemical">N-heteroaryl aldehydes or <span class="Chemical">ketones [reaction conditions: 2-acetylpyridine (0.10 mmol), benzyl amine (0.10 mmol), solvent (2 mL), catalyst (15 mg), 10 h, 80 °C].

Scope of Substrates

On the basis of these promising screening results, we next scrutinized the scope of the <span class="Chemical">current procedure by testing several <span class="Chemical">pyridine aldehyde or ketone derivatives and amines using the graphene oxide-supported copper catalyst. First, we evaluated the scope of amine derivatives bearing either electron-donating or electron-withdrawing groups under the optimized reaction conditions, and the results are demonstrated in Table . It was found that amines containing electron-withdrawing or electron-donating groups gave moderate to good conversion percentages of the desired products. Subsequently, a series of N-heterocyclic aldehydes or ketones were examined as reaction partners. The results indicated that a diverse range of N-heterocyclic aldehydes or ketones were all compatible with this transformation showing moderate to good conversion percentages. The most important feature of the present approach is that this tandem reaction is devoid of unwanted side products.

Table 1

Transannulation of N-Heterocyclic Aldehydes or Ketones and Alkylamines Using Cu@AA@APTES@GO as a Catalysta

Reaction conditions: N-heteroaryl aldehydes or ketones (0.10 mmol), alkylamines (0.10 mmol), acetonitrile (2 mL), catalyst (15 mg), 10 h, 80 °C.

Conversion percentage was determined by GC–MS.

TON is the number of moles of product per mole of catalyst.

Reaction conditions: N-heteroaryl <span class="Chemical">aldehydes or <span class="Chemical">ketones (0.10 mmol), alkylamines (0.10 mmol), acetonitrile (2 mL), catalyst (15 mg), 10 h, 80 °C.

Mechanism

A plausible catalytic cycle on the ban class="Chemical">sis of previous literature reports has been proposed and is shown in Scheme . First, the condensation reaction between N-heteroarene aldehyde or ketone and alkylamine generates complex A.[32] In the next step, complex B is formed via the coordinative interaction of copper(II) with the pyridyl N-atom of complex A. Thereafter, oxidative dehydrogenation of complex B in the presence of copper(II) generates complex C which undergoes isomerization to give complex D that eventually eliminates the imidazo[1,5-a]pyridine product by giving Cu species. Finally, the catalyst is regenerated back via the removal of water.[77]

Scheme 2

Plausible Mechanism for the Transannulation of N-Heterocyclic Aldehydes and Alkylamines Using Cu@AA@APTES@GO as a Catalyst

Catalytic Activity Tests

Reusability of a catalyst is an important aspect from the commercial point of view as it increases the potentiality of the catalyst. In order to take advantage of the heterogeneous nature, the recyclability of the <span class="Chemical">Cu@AA@<span class="Chemical">APTES@GO nanocatalyst was investigated for the test reaction. In order to do so, after completion of the reaction, the catalyst was easily recovered from the reaction media by means of centrifugation and used for the next catalytic cycles without any additional treatment. Thanks to the high stability of the graphene oxide-supported copper nanocatalyst that could catalyze the full conversion of test substrates during all repeated cycles without any significant loss in catalytic activity (Figure ). This observation was further supported by SEM, TEM, and FT-IR analysis of the recovered catalyst (Figures S1, S2, and S7) which showed that the structure of recovered catalyst remained unchanged in comparison to fresh catalyst that provided a concrete proof of the excellent stability of the catalyst.

Figure 11

Catalyst recycle runs for the transannulation of N-heterocyclic aldehydes and alkylamines [reaction conditions: 2-acetylpyridine (0.10 mmol), benzyl amine (0.10 mmol), acetonitrile (2 mL), catalyst (15 mg), 10 h, 80 °C].

Catalyst recycle runs for the transannulation of <span class="Disease">N-heterocyclic <span class="Chemical">aldehydes and alkylamines [reaction conditions: 2-acetylpyridine (0.10 mmol), benzyl amine (0.10 mmol), acetonitrile (2 mL), catalyst (15 mg), 10 h, 80 °C].

In order to verify that the observed catalysis was due to the <span class="Chemical">graphene oxide-supported <span class="Chemical">copper nanocatalyst rather than leached copper species in solution, a hot filtration experiment of test reaction was carried out. The solid catalyst was removed from the reaction mixture with the assistance of centrifugation after 5 h (half the reaction time), and the reaction was continued with the solid-free filtrate for an additional 5 h. Subsequently, the supernatant was analyzed by GC–MS in order to find out the conversion percentage, and it was observed that the reaction had reached 62% completion at the end of 5 h. There was no appreciable change in the conversion percentage of the desired product when the supernatant was subjected to further stirring after removing the solid catalyst from it. The GC–MS results showed that the reaction was hard to occur even after prolonged time as the removal of catalyst had stopped the reactivity. Thus, these results demonstrated that there was no loss of catalytic components during the course of reaction.

Comparison of the Catalytic Activity of Cu@AA@APTES@GO with the Previously Reported Catalytic Systems

In order to compare the advantages of the present approach, an extensive study of previous literature precedents was carried out for the transannulation of n class="Chemical">N-heteroaryl aldehydes or ketones with alkylamines. It is important to note that all of the earlier catalysts employed for the concerned reaction were homogeneous and had serious limitations. A homogeneous catalyzed reaction mixture could lead to the formation of inactive dimers or aggregates which obstructed the catalytic active sites, thereby hampering its activity. Besides, it is clearly evident from Table that graphene oxide-based copper catalyst revealed good catalytic results in comparison to other catalysts employed till date. Moreover, homogeneous catalysts could not be recovered as they undergo decomposition immediately after the completion of the reaction and could not be reused for further cycles. On the contrary, the graphene oxide-based copper nanocatalysts could be recovered easily via centrifugation and recycled for six consecutive cycles without any significant loss in its catalytic activity.

Table 2

Comparison of Catalytic Activity of Cu@AA@APTES@GO with Other Catalyst Reported in the Literature for Transannulation of N-Heteroaryl Aldehydes or Ketones with Alkylamines

Conclusions

In summary, we have successfully developed a new heterogeneous catalyst that is composed of exfoliated <span class="Chemical">2D <span class="Chemical">graphene oxide-based nanomaterial for transannulation of <span class="Chemical">N-heteroaryl aldehydes or ketones with alkylamines. We employed a simple and general route for the immobilization of copper complex onto amine-functionalized graphene oxide nanosheets for the synthesis of the Cu@AA@APTES@GO nanocatalyst. The presence of abundant oxygenated hydroxyl functional groups on basal planes of exfoliated 2D graphene oxide nanocomposites provides very effective and powerful sites for the loading of Schiff base metal complex. It exhibits significantly improved catalytic efficiencies which could be accredited to the presence of nanometer size of support material and 2D confinement that provides a large number of catalytically active sites. Further, the efficacy of the synthesized Cu@AA@APTES@GO catalyst can also be realized by focusing on the results of various catalytic activity tests conducted which include simple work up procedure, substrate scope, hot filtration, and recyclability experiments. Consequently, this methodology offers a new approach for the transannulation of N-heteroaryl aldehydes or ketones with alkylamines using graphene oxide-supported copper catalyst under mild reaction conditions.