A sustainable avenue for the synthesis of propargylamines and benzofurans using a Cu-functionalized MIL-101(Cr) as a reusable heterogeneous catalyst

A heterogeneous copper-catalyzed A3 coupling reaction of aldehydes, amines, and alkynes for the synthesis of propargylamines and benzofurans has been developed. Here, the modified metal–organic framework MIL-101(Cr)-SB-Cu complex was chosen as the heterogeneous copper catalyst and prepared via post-synthetic modification of amino-functionalized MIL-101(Cr). The structure, morphology, thermal stability, and copper content of the catalyst were determined by FT-IR, PXRD, SEM, TEM, EDX, TGA, XPS, and ICP-OES. The catalyst shows high catalytic activity for the aforementioned reactions under solvent-free reaction conditions. High yields, low catalyst loading, easy catalyst recovery and reusability with not much shrink in catalytic activity, and a good yield of 82% in gram-scale synthesis are some of the benefits of this protocol that drove it towards sustainability.


A sustainable avenue for the synthesis of propargylamines and benzofurans using a Cu-functionalized MIL-101(Cr) as a reusable heterogeneous catalyst
Fillip Kumar Sarkar 1 , Lenida Kyndiah 1 , Sushmita Gajurel 1 , Rajib Sarkar 1 , Samaresh Jana 2 & Amarta Kumar Pal 1* A heterogeneous copper-catalyzed A 3 coupling reaction of aldehydes, amines, and alkynes for the synthesis of propargylamines and benzofurans has been developed.Here, the modified metalorganic framework MIL-101(Cr)-SB-Cu complex was chosen as the heterogeneous copper catalyst and prepared via post-synthetic modification of amino-functionalized MIL-101(Cr).The structure, morphology, thermal stability, and copper content of the catalyst were determined by FT-IR, PXRD, SEM, TEM, EDX, TGA, XPS, and ICP-OES.The catalyst shows high catalytic activity for the aforementioned reactions under solvent-free reaction conditions.High yields, low catalyst loading, easy catalyst recovery and reusability with not much shrink in catalytic activity, and a good yield of 82% in gram-scale synthesis are some of the benefits of this protocol that drove it towards sustainability.
Propargylamines have wide applications in organic synthesis as they are used as an essential intermediate for the synthesis of various biologically active compounds such as peptides, β-lactams, allylamines, natural products, drug molecules, agrochemical products, etc [1][2][3][4] .They are also used as precursors for the synthesis of a variety of heterocyclic compounds such as quinolines 5 , phenanthrolines 6 , pyrroles 6 , etc.In addition, propargylamine scaffolds are found in commercially available drugs such as rasagiline and deprenyl and are also used for the treatment of Parkinson's and Alzheimer's disease [7][8][9] .On the other hand, benzofurans are significant oxygen-containing heterocyclic scaffolds that exhibit immense biological and pharmaceutical activities such as anti-inflammatory 10 , anticancer 11 , antifungal 12 , antitumor 13 , etc.They are not only pivotal structural subunits in naturally occurring bioactive compounds but also act as a useful synthons in the synthesis of many natural products [14][15][16] .Moreover, benzofurans have several applications in cosmetic formulations and optical brighteners 17 .Therefore, efforts have been made by researchers to develop methodologies to synthesize propargylamines and benzofurans moieties.Some of the reported synthetic procedures for the synthesis of benzofurans are reactions of 2-chlorophenols with terminal alkynes 18 , cyclizations of ketones 19 , the sigmatropic rearrangement of arene 20 , palladium-catalyzed cyclizations of phenols 21 , etc.A recent synthetic approach is the transition-metal catalyzed coupling of aldehydes, amines, and alkynes (known as the A 3 coupling reaction) which generally produce propargylamines [22][23][24][25][26][27] .However, benzofurans can also be synthesized by an A 3 coupling reaction followed by intramolecular cyclizations [28][29][30][31][32][33][34][35] .Therefore, sustainable development of methodologies for the synthesis of these Spectroscopic studies.After the preparation of the MIL-101(Cr)-SB-Cu (III), it was well characterized by various spectroscopic techniques such as Fourier transform infrared (FT-IR) spectroscopy, powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive X-ray (EDX), X-ray photoelectron spectroscopy (XPS).Thermal stability was determined by thermogravimetric analysis (TGA), and the copper content in the catalyst was examined by inductively coupled plasma optical emission spectroscopy (ICP-OES).
The FT-IR spectra of the MIL-101(Cr)-NH 2 (I), MIL-101(Cr)-SB (II), and MIL-101(Cr)-SB-Cu (III) are presented in Fig. 3.In Fig. 3a-c band at around 1570 cm −1 is associated with the C=C stretching vibration of the benzene ring.Further, the band observed at around 1695 cm −1 (Fig. 3c) and 1698 cm −1 (Fig. 3b) corresponds to the azomethine group (> C=N-) present in the framework.However, a slight shifting of > C=N-band (Fig. 3c) to a lower value endorses the coordination of the Cu 2+ to the azomethine-N of the Schiff base moiety 62 4416) planes respectively, which are in accordance with that of the literature and therefore, confirm its successful preparation 55,[63][64][65][66] .In the PXRD pattern of MIL-101(Cr)-SB-Cu (III), the presence of peaks at 2θ values of 5.1°, 8.6°, and 17.5° corresponding to MIL-101(Cr)-NH 2 peaks implies that the structure of the parent MOF is retained even after the post-synthetic modification including functionalization and metal complexation.
The structural morphology of the prepared MIL-101(Cr)-SB-Cu (III) catalyst was investigated using SEM and TEM analysis.The SEM image as depicted in Fig. 5a, shows irregular agglomerated morphology of the prepared MIL-101(Cr)-SB-Cu (III) catalyst.The TEM images from low to high magnifications are illustrated in Fig. 5b-c.In the TEM image, the black spherical shape indicates the agglomeration of the Cu in the MOF.6b), the peaks around 933.9 and 953.7 eV corresponds to Cu 2p 3/2 and Cu 2p 1/2 respectively, which indicates that the oxidation state of Cu is + 2.Besides these, the satellite peaks at 942.7 and 962.6 eV in Cu 2p also indicate the presence of Cu(II) species 33,67 .
The thermal stability of the prepared MIL-101(Cr)-SB-Cu (III) catalyst was studied using thermogravimetric analysis.The TGA thermogram of MIL-101(Cr)-NH 2 (I) and MIL-101(Cr)-SB-Cu (III) are demonstrated in Fig. 7.The TGA thermogram of the MIL-101(Cr)-NH 2 (I) exhibits weight loss at around 100 °C which is due to the loss of absorbed water.A major weight loss process is observed within the temperature 250-500 °C which may be due to the decomposition of the MOF structure.The data is similar to that of the reported value which indicates that the MIL-101(Cr)-NH 2 (I) is stable up to 250 °C68 .Similarly, the TGA thermogram of catalyst (III) is also consistent with that of the parent MIL-101(Cr)-NH 2 (I) suggesting that the thermal stability of the catalyst (III) is sustained even after the post-synthetic modification and functionalization of the MOF.Furthermore, ICP-OES analysis was carried out to check the Cu content in the prepared MIL-101(Cr)-SB-Cu (III) catalyst which was found to be 4.23 wt%.

Catalytic activity studies.
The prepared MIL-101(Cr)-SB-Cu was then utilized for catalytic application.
Next, the model reaction was performed with different catalyst amounts from 0 to 20 mg under SFRC (Table 1, entry 8-11).The best yield of 86% of product 4a was obtained with 15 mg of the catalyst.Furthermore, increasing the amount of catalyst to 20 mg, there was no increment in the yield of product 4a.On the other hand, a lower amount of catalyst (< 15 mg) furnished a lower yield of the product (Table 1, entries 8 and 9).As expected, product 4a was not formed in the absence of a catalyst (Table 1, entry 11).Eventually, at lower temperatures such as 60 °C, and 80 °C, the lower yield of product 4a was obtained (Table 1, entries 12 and 13).Thereafter, increasing the temperature to 120 °C also did not enhance the yield of product 4a (Table 1, entry 14).Moreover, MIL-101(Cr)-NH 2 and MIL-101(Cr) also did not produce the desired product 4a (Table 1, entry 15).After optimization of the suitable reaction condition, the generality of the methodology was explored using different aryl aldehydes.Aryl aldehydes containing -CH 3 , -OCH 3 , -F, -Cl, -Br afforded the corresponding products in good to excellent yields (85-96%) (Fig. 8, 4a-4k).Further, 2-furaldehyde and trans-cinnamaldehyde also produced the desired products in good yields (Fig. 8, 4l, and 4m).Morpholine as the secondary base and  www.nature.com/scientificreports/phenylacetylene as the alkynes afforded good yields.However, when primary amine such as aniline was used, no desired product was obtained.Further, piperidine and diethyl amine produced a trace amount of products.
The catalytic activity of MIL-101(Cr)-SB-Cu was further studied for the synthesis of benzofurans where 2-hydroxybenzaldehyde (1d), morpholine (2a), and phenylacetylene (3a) were chosen as the model substrates for optimization of the reaction condition.Therefore, to optimize the reaction condition, different solvents, temperature, and catalytic loading were investigated and the results are summarized in Table 2. Initially, the reaction was performed with MIL-101(Cr)-SB-Cu (15 mg) in the presence of DMAP in toluene under refluxed condition, and the benzofuran 5a was obtained in 84% yield with a trace amount of propargylamine 4d (Table 2, entry 1).However, in the absence of DMAP, the propargylamine 4d was obtained in 87% yield and failed to produce the benzofuran 5a (Table 2, entry 2).This might be due to the low nucleophilicity of the hydroxyl group of 2-hydroxybenzaldehyde.Hence, DMAP acts as the base which facilitates the intramolecular nucleophilic attack by abstracting the proton from the hydroxyl group to give the benzofuran products.To inspect the effect of solvent on the model reaction, several solvents including solvent-free reaction conditions (SFRC) were screened.Fortunately, an excellent yield of 92% of product 5a was achieved in solvent-free reaction condition in 6 h (Table 2, entry 3).Further, EtOH afforded product 5a in trace amount and the uncyclized product 4d in 42% yield (Table 2, entry 4).In the case of CHCl 3 , product 5a was not formed and only a trace amount of 4d was observed in TLC (Table 2, entry 5).However, solvents like CH 3 CN, DCE, and H 2 O provided 4d in 45%, 37%, and 20% yields respectively with a trace amount of 5a (Table 2, entries 6-8).Henceforth, the reactions were further performed in SFRC.Thereafter, different catalyst concentration was also examined.In the absence of a catalyst, no product formation was detected (Table 2, entry 9).When the reactions were carried out with 5, 10, 15, and 20 mg of the catalyst, product 5a was obtained in 74%, 86%, 92%, and 92% yields respectively (Table 2, entries 10-12).The best result was obtained with 15 mg of the catalyst and further increasing the amount of catalyst no increment in the yield of the product was observed.After that, the effect of different amounts of DMAP on the model reaction was checked and the best result was obtained with 0.5 equiv. of DMAP (Table 2, entries 13 and 14).Other bases like Na 2 CO 3 , K 2 CO 3 , and Cs 2 CO 3 were also screened.Na 2 CO 3 afforded 26% yield of the product 5a along with 67% yield of 4d (Table 2, entries 15).In case of K 2 CO 3 and Cs 2 CO 3 , the products 5a were obtained in 67% and 81% yields respectively along with trace amount of 4d in both the cases (Table 2, entries 16 and 17).Finally, the impact of temperature was investigated and the highest yield of the desired product 5a was achieved at 100 °C.Lowering the temperature from 100 to 60 °C afforded a lower yield of the product whereas high temperature (120 °C) did not improve the yield of the product 5a (Table 2, entries 18-20).In summary, After optimization of the suitable reaction condition, the versatility of the present protocol was explored with various substituted 2-hydroxybenzaldehyde containing electron-withdrawing groups and electron-donating groups (Fig. 9, 5a-5k).In all the cases, the products were obtained in good to excellent yields (86-95%).Further, electron-withdrawing groups provided slightly better yields of the products (5f and 5k) than electron-donating groups (5b, 5c, 5i, and 5j).However, aliphatic alkynes such as 1-octyne, and 1-pentyne did not produce the target products.Morpholine as the secondary amine afforded the desired products in good to excellent yields but aniline, diethyl amine, and piperidine were unable to produce the desired products.

Plausible mechanism.
A schematic representation of a plausible mechanism for the synthesis of propargylamines and benzofurans is presented in Fig. 10  Scale-up reaction.Gram-scale synthesis was carried out to check the possibility of industrial application (Fig. 11).Therefore, the reaction was performed using 2-hydroxybenzaldehyde (1d, 9 mmol, 1.080 g), morpholine (2a, 10.8 mmol, 0.940 g), phenylacetylene (3a, 13.5 mmol, 1.377 g), DMAP (4.5 mmol, 0.549 g) and MIL-101(Cr)-SB-Cu (135 mg) under the optimized reaction condition.After that, the reaction mixture was purified and the desired product was obtained in 82% yield.This good result refers the protocol for industrial application.
Reusability of the catalyst.Easy separation and reusability of the catalyst are important parameters of a heterogeneous catalyst.Therefore, the reusability of the catalyst was studied for the synthesis of benzofuran (5a) using 2-hydroxybenzaldehyde (1d), morpholine (2a), and phenylacetylene (3a) under the optimized reaction condition.After 6 h, ethyl acetate was added to the reaction mixture, and the catalyst was separated by centrifugation followed by filtration.The recovered catalyst was washed with ethyl acetate, ethanol, and diethyl ether and dried properly.Thereafter the recovered catalyst was used in another set of reactions.The catalyst was reused for up to five consecutive runs.It was noticed that the recovered catalyst offered good yield till five runs (Fig. 12).The structural morphology and stability of the reused MIL-101(Cr)-SB-Cu (III) catalyst (after 5th run) were studied using various spectroscopic techniques such as FT-IR (Fig. 13), SEM (Fig. 14a), TEM (Fig. 14b), TGA (Fig. 15), and ICP-OES.From the FT-IR spectrum (Fig. 13) of the reused catalyst no notable changes in the characteristic bands were observed.The SEM (Fig. 14a) and TEM (Fig. 14b) images of the reused catalyst give evidence of some aggregation of the Cu particles.Further, the TGA thermogram (Fig. 15) of the reused catalyst Comparative study.The present protocol for the synthesis of benzofurans has been compared with those of previously reported methods in the literature.The comparative summary is illustrated in Table 3. From Table 3, it can be concluded that the present protocol also shows better result as that of the reported methods.

Conclusion
In conclusion, an efficient and sustainable protocol for the synthesis of propargylamines and benzofurans via A 3 coupling and cycloisomerization reaction of aldehydes, amines, and alkynes has been developed utilizing MIL-101(Cr)-SB-Cu as an easily recoverable and reusable heterogeneous catalyst.A series of propargylamine and benzofuran derivatives were synthesized bearing different electron-donating and electron-withdrawing groups.High yields, operational simplicity, and solvent-free reaction condition are some of the advantages of this methodology.The catalyst could be easily separated by centrifugation followed by filtration and shows excellent catalytic activity up to five consecutive runs.The gram-scale synthesis also provided a high yield of 82% implying its possibility for application at the industrial level.

Experimental section
General information.All the chemicals required were obtained from Sigma-Aldrich, Alfa Aesar, Spectrochem, and TCI and used without further purification.FT-IR spectra were recorded on a Bruker Alpha II system (ν max in cm −1 ) on KBr disks. 1 H NMR and 13 C NMR (400 MHz and 100 MHz respectively) spectra were recorded using a Bruker Avance II-400 spectrometer using CDCl 3 as the solvent (chemical shifts in δ with TMS as internal standard).Powder XRD analyses were carried out using a Bruker D8 Advance and Rigaku Ultima IV XRD instrument.Transmission Electron Microscopy (TEM) analysis was carried out using a JEOL JSM 100CX system.Scanning electron microscopy (SEM) and Energy Dispersive X-ray (EDX) analysis were carried out using a JSM-6360 (JEOL) system.X-Ray Photoelectron Spectroscopy (XPS) was performed using a PHI 5000 VersaProbe III system.Thermogravimetric analysis (TGA) was carried out using a Perkin Elmer Precisely STA 6000 simultaneous thermal analyzer.Inductively coupled plasma optical emission spectroscopy (ICP-OES) was carried out using Thermo Scientific™ iCAP™ 7600 instrument.TLC Silica gel 60 F 254 (Merck) was used for TLC analysis.Hexane refers to the fraction boiling between 60 and 80 °C.To that, 1.60 g of Cr(NO 3 ) 3 .9H 2 O and 0.72 g of 2-aminobenzene-1,4-dicarboxylic acid (NH 2 -H 2 DBC) were added slowly under constant stirring at room temperature for 30 min.After that, the mixture was transferred into a 50 mL Teflon-lined stainless steel autoclave and kept at 150 °C in a muffle furnace for 12 h.Then, the obtained green powder was collected by filtration and washed thoroughly with H 2 O, DMF, and ethanol respectively.Eventually, the MIL-101(Cr)-NH 2 was dried at 100 °C.This dried 0.40 g of MIL-101(Cr)-NH 2 (I) was dispersed in 30 mL of ethanol.Then, pyridine-2-carboxaldehyde (0.57 mL) was added dropwise to the mixture and refluxed for 24 h with constant stirring.Finally, the MIL-101(Cr)-SB (II) was obtained by centrifugation, filtration and washed properly with ethanol, diethyl ether, and dried.Thereafter, 0.40 g of MIL-101(Cr)-SB (II) was dispersed in 30 mL of ethanol.To that mixture, Cu(OAc) 2 •H 2 O (0.25 g) was added and the solution was refluxed for 24 h with constant stirring.After that, the obtained solid materials were centrifuged, filtered, and washed with ethanol, and diethyl ether, and it was dried to get the resulting MIL-101(Cr)-SB-Cu (III) complex.
General procedure for the synthesis of propargylamines.In a 25 mL round bottom flask, aryl aldehydes (1, 1 mmol), secondary amines (2, 1.2 mmol), and MIL-101(Cr)-SB-Cu (III) [15 mg] were taken and stirred at 100 °C under SFRC for 15 min.Then, aryl acetylenes (3, 1.5 mmol) were added dropwise to the reaction mixture and stirring was continued for 45 min.Then, 10 mL of ethyl acetate was added to the reaction mixture and the catalyst was separated by centrifugation followed by filtration.The organic solvent was evaporated under reduced pressure and the crude products were further purified by column chromatography (silica gel 100-200 mesh) using ethyl acetate/hexane (1:19) as eluent.
General procedure for the synthesis of benzofurans.A mixture of substituted 2-hydroxybenzaldehydes (1, 1 mmol), secondary amines (2, 1.2 mmol), and MIL-101(Cr)-SB-Cu (III) [15 mg] was taken in a 25 mL round bottom flask and stirred at 100 °C under SFRC for 15 min.Then, aryl acetylenes (3, 1.5 mmol) were added dropwise into the reaction mixture and continued the stirring for another 45 min.Then, DMAP (0.5 mmol) was added to the reaction mixture, and the stirring was continued for 5 h.After that, ethyl acetate (10 mL)  www.nature.com/scientificreports/ was added to the reaction mixture, and the catalyst was separated by centrifugation followed by filtration.The organic solvent was washed with H 2 O (2 × 5 mL), and brine (1 × 5 mL), and dried over anhydrous Na 2 SO 4. The organic solvent was evaporated under reduced pressure and the crude products were further purified by column chromatography (silica gel 100-200 mesh) using ethyl acetate/hexane as eluent.