Copper (triazole-5-yl)methanamine complexes onto MCM-41: the synthesis of pyridine-containing pseudopeptides through the 6-endo-dig cyclization of 1,5-enynes

An efficient approach for the synthesis of immobilized copper (triazole-5-yl)methanamine complexes onto MCM-41 (Cu@TZMA@MCM-41), as a novel recyclable nanocatalyst, is described. This nanocatalyst was used for the synthesis of pyridine-containing pseudopeptides through a sequential Ugi/nucleophilic addition/1,5-enyne cyclization reaction and elicited good-to-excellent yields. The nanocatalyst was fully characterized by SEM, EDS, TEM, BET, ICP-OES, TGA, and XRD techniques. Furthermore, the catalyst was recovered by simple filtration and could be used for at least 5 cycles without significant loss of activity.

In recent years, depending on the structure of the starting 1,n-enynes, reaction conditions, and different types of metal catalysts (e.g., Pt, 18 Au, 7,19 Cu, 20 Fe, 21 Bi, 22 Rh 23 and Ag 24 ), various nitrogen-containing heterocyclic compounds have been synthesized. 25 Nevertheless, the separation and recycling of homogenous metal catalysts from the product is a major drawback limiting wider application of these compounds.
The design of efficient and reusable heterogeneous catalysts (particularly for C-C and C-heteroatom coupling reactions) has become important. 26 However, support of homogeneous catalysts on various solid supports is disadvantageous due to the reduction in catalytic activity. Hence, strategies have focused on using nanoparticles as ideal and efficient heterogeneous supports. 27 Among various nanomaterials, mesoporous silica (e.g., MCM-41) due to having nano-sized pores, high pore volume, specic surface area, non-toxic content, and good thermal and mechanical stability, has been employed as a support.
Meanwhile, several MCM-41-supported copper complexes have been reported and used as heterogeneous catalysts in organic synthesis. 28 The design of sequential multiple components and cyclization reactions are powerful approaches for the synthesis of structurally complex and functionally diverse heterocyclic compounds. 29 Recently, the Ugi post-transformation reaction has been shown to be a powerful reaction for facile synthesis of novel heterocyclic skeletons under simple and mild reaction conditions that could open up new areas in drug synthesis. 30 Meanwhile, this method is known for the synthesis of multifunctionalized compounds.
We have a strong interest in designing post-transformation reactions. 31 Herein, we report an efficient, mild and facile procedure to provide 1,5-enynes and design of novel cyclization reactions in the presence of a new nano heterogeneous catalyst for the synthesis of a pyridine skeleton. We introduced a new strategy for the synthesis of a pyridine-containing pseudopeptides backbone through sequential Ugi/nucleophilic addition/ 1,5-enyne cyclization reaction. We immobilized Cu (triazole-5yl)methanamine complexes onto MCM-41 (Cu@TZMA@MCM-41) as a novel nanocatalyst (Scheme 1 and 2).
The XRD spectroscopy patterns at a low angle of the MCM-41 support and supported catalysts are illustrated in Fig. 2. The diffractograms of samples exhibited three peaks: an intense diffraction peak for the d 100 plane at 2q ¼ 2.58 and two weak diffractions for d 110 and d 200 planes at 2q ¼ 4.41 and 5.13 , respectively. Aer functionalization of MCM-41 channels, peak intensities were decreased, which conrmed incorporation of the copper complex onto MCM-41 channels and that the structural integrity of the mesoporous had been retained.
SEM images of MCM-41 ( Fig. 3a) and Cu@TZMA@MCM-41 (Fig. 3b) demonstrated that these catalysts had been formed as spheres. Furthermore, upon functionalization of MCM-41, the surface morphology of the nanocatalyst was not changed signicantly.
TEM images of some of the samples clearly illustrated the well-ordered arrangement of pores. As shown in Fig. 4, copper graing did not change the periodicity of the hexagonally mesoporous structure.
The EDX spectrum indicated support of copper particles onto the MCM-41 surface (Fig. 5). Furthermore, ICP-OES was used to ascertain the percentage of copper particles immobilized on the mesoporous catalyst. The loading amount of copper in the catalyst was found to be 3.9%.
The textural parameters of MCM-41 and Cu@TZMA@MCM-41 were investigated using nitrogen adsorption-desorption ( Fig. 6). Based on the IUPAC classication, both samples demonstrated type-IV isothermal curves, which are related to mesoporous structures. Aer functionalization of the pores of MCM-41, the pore volume, surface area and wall diameter of MCM-41 and Cu@TZMA@MCM-41 was found to be 1.3 and 0.8 cm 3 g À1 , 985 and 470 m 2 g À1 , and 1.06 and 2.81 nm, respectively. Hence, the total pore volume and specic surface area were decreased, and the wall diameter was increased. These data were attributed to graed organic moieties and copper on pore channels.
Thermograms were used to determine the weight changes of catalysts before and aer modication of synthesized mesoporous silica (Fig. 7). The rst step of weight loss (at <200 C) corresponded to removal of physically absorbed water and organic solvents. The next step of weight loss occurred upon increasing the temperature to 800 C: this was related to decomposition of immobilized organically modied moieties and silanol groups.   Aer nanocatalyst generation, we attempted the synthesis of new functionalized 1,5-enynes. To achieve this goal, in the initial study, the Ugi 4-CR of 4-nitroaniline 1h, benzaldehyde 2h, propiolic acid 3h, and cyclohexyl isocyanide 4h in MeOH at room temperature was selected as a model reaction. In the structure of the product 5h, there was an alkyne moiety that had high potential for nucleophilic addition. Then, propargylamine was added to the crude Ugi-adduct 5h in the same reaction vessel. There were two possibilities for the nucleophilic addition of propargylamine to an alkyne moiety that led to the synthesis of two diastereomers of 6h (E : Z 78 : 22). The ratio of the isomers was ascertained using 1 H nuclear magnetic resonance (NMR) spectroscopy.
Finally, without separating 1,5-enyne 6h, the solvent was evaporated and then the reaction was investigated for 6-endodig cyclization in the presence of various amounts of nanocatalysts (  entry 4). Also, comparison of the activity of Cu@TZMA@MCM-41 and Cu/C in the model reaction was investigated: the yield of the desired product in the presence of Cu/C was only 50%.
Based on observations stated above, we evaluated the scope and limitations of this newly developed protocol. Hence, various Ugi adducts were synthesized from propiolic acid and    This journal is © The Royal Society of Chemistry 2020 RSC Adv., 2020, 10, 10577-10583 | 10579 several aniline derivatives, benzaldehydes, and isocyanides, and subjected to the sequential Ugi-4CR/intermolecular nucleophilic addition/cyclization reaction in the presence of Cu@TZMA@MCM-41 at high yields ( Table 2).
The structures of three compounds, 6b, h and n, were selected and determined by spectroscopy (Fourier transforminfrared (FT-IR), 1 H NMR, 13  On the basis of work by Abbiati and colleagues, 32 a plausible reaction mechanism is shown in Scheme 3. The N-substituted-2-alkynamide intermediate (I) had high affinity towards intramolecular nucleophilic addition. Propargylamine was added to activate the triple bond to furnish a mixture of two  The substrate scope for the synthesis of the pyridine-containing pseudopeptides 7a-n Simple recovery and recyclability are valuable properties of catalysts. Therefore, the reusability of the catalyst was studied in the 6-endo-dig cyclization reaction of 1,5-enynes. Hence, aer completion of the reaction, the nanocatalyst was easily separated via ltration and washed several times with EtOAc and reused directly in the next runs (up to ve times) using the same process without a change in catalytic activity. The exact amount of copper was measured by ICP-EOS, and showed that the amount of copper had decreased from 3.9% at the rst run to 3.8% aer ve recycles.

General remarks
The reagents and solvents used in this project were purchased from various chemical companies and were used directly without additional purication. The reactions were monitored by thin-layer chromatography (TLC) over gel-60 F 254 plates. Chromatography columns were packed using 63-200 mesh ASTM silica gel. Melting points were measured via an electrothermal 9100 apparatus. FT-IR spectroscopy was done using KBr disks in a AABFT-IR (FTLA 2000) spectrophotometer. 1 H NMR (300 and 600) and 13 C NMR (75 MHz) spectra were recorded with a Bruker spectrometer. High-resolution mass spectra of the products were recorded with an Agilent quadrupole time-of-ight liquid chromatography/mass spectrometry system. XRD spectroscopy patterns of as-prepared samples were obtained by an XPert Pro Panalytical setup. The morphology and size of particles were recorded using a scanning electron microscope (Zeiss-SIGMA VP). TEM images were obtained by a Zeiss EM10C (100 kV) system. The specic surface area and pore size of the synthesized nano-catalyst were determined by N 2 sorption-desorption. The TGA curves of samples were obtained using a Shimadzu DTG-60 instrument. The copper content of the nanocatalyst was determined ICP-OES. The elemental analysis of the catalyst was achieved by EDX using a Zeiss SIGMA VP system.

Preparation of ligand ((triazole-5-yl)methanamine)
To a stirring solution of phthalimide (3.4 mmol) and K 2 CO 3 (5.1 mmol) in CH 3 CN (12 mL) was added propargyl bromide (5.8 mmol) under reux. Aer 48 h, the hot mixture was ltered and cooled at room temperature. The solvent was concentrated under reduced pressure. The resulting residue was puried by direct crystallization to afford N-prop-2-ynylphthalimide (A) as a colourless solid. Subsequently, the reaction of N-prop-2ynylphthalimide (1 mmol) with TMSN 3 (1.5 mmol) in DMF : H 2 O (9 : 1) (3 mL) was carried out in the presence of CuI (10 mol%) at 100 C. Reaction progress was monitored using TLC and, aer the reaction had nished, the reaction mixture was extracted with ethyl acetate. The organic phase was dried over Na 2 SO 4 and the solvent was evaporated under vacuum. The crude residue was puried by silica-gel column chromatography to give the desired product. Finally, to a solution of the product (3.7 mmol) in EtOH (10 mL) was added hydrazine hydrate (3.7 mmol) and stirred under reux for 3 h. Aer cooling and ltration, the ltrate was acidied with HCl, and ltered once more. The volatile solvent of the ltrate was removed and (triazole-5-yl) methanamine was crystallized as salts from ethyl acetate.

Synthesis of Cu@TZMA@MCM-41
Preparation of Cu@TZMA@MCM-41 was carried out in four steps. In the rst step, according to the literature, MCM-41 was synthesized using a sol-gel protocol. 33 Briey, in a roundbottomed ask (500 mL), 1.75 mL of NaOH (2 M) solution was added to 240 mL of deionized water with stirring and heating at 80 C. Next, 0.5 g (1.37 mmol) of the surfactant cetyltrimethylammonium bromide (CTAB) was added. Aer homogenization of the solution, 2.5 mL of tetraethyl orthosilicate (TEOS) was dropped slowly into the solution, to prepare a white slurry. The obtained mixture was reuxed for 2 h under continuous stirring. Aer cooling to room temperature, the resulting mixture was separated by ltration, washed with deionized water, and calcined at 600 C for 5 h at a rate of 2 C min À1 . In the second step, silanization of the synthesized MCM-41 (2.4 g) was carried out by reuxing of 3-chloropropyl trimethoxysilane (CPTMS) (2.5 g) in n-hexane (48 mL) under a N 2 atmosphere and stirring for 24 h. The obtained solid Cl-(CH 2 ) 3 @MCM-41 was washed thrice with n-hexane and dried under vacuum. In the third step, in a 50 mL round-bottomed ask, under continuous stirring, Cl-(CH 2 ) 3 @MCM-41 (0.5 g), (triazole-5-yl)methanamine (1 mmol) and Et 3 N (1 mL) were added to DMF (20 mL) at 100 C for 30 h to afford (triazole-5-yl) methanamine@MCM-41. Then, the prepared TZMA@MCM-41 was ltered and washed several times by ethanol and dried in a vacuum oven. Finally, a mixture of the resulting TZMA@MCM-41 (1.5 g) and CuCl 2 anhydrous (0.5 g) was dispersed in EtOH (25 mL) under ultrasonic agitation for 20 min and stirred under reux for 20 h. Then, the nano-catalyst (Cu@TZMA@MCM-41) was separated and washed thoroughly using ethanol and dried under a vacuum.
General procedure for preparation of pyridine-containing pseudopeptides in the presence of Cu@TZMA@MCM-41 (7an) Primary amine (1 mmol), aldehyde (1 mmol) and 2 mL of MeOH were added to a 25 mL round-bottomed ask equipped with a magnetic stirrer at room temperature. Aer 15 min, propiolic acid (1 mmol) was added to the reaction ask and stirring was continued for 5 min. Isocyanide (1 mmol) was added and the mixture stirred at ambient temperature for 1 day. Reaction progress was monitored using TLC. Upon reaction completion, without isolation or purication, propargylamine was added to the Ugi mixture. The reaction mixture was stirred at 60 C for 8 h. Aer reaction completion, the solvent was removed using a rotary evaporator. Without purication, DMSO (2 mL) and Cu@TZMA@MCM-41 (7 mg, 0.43 mmol%) were added to the ask and the reaction mixture stirred at room temperature. Reaction progress was monitored using routine TLC. Upon reaction completion, the nano-catalyst was separated by ltration and recycled as such for the next experiment. The mixture was diluted with water and EtOAc. The organic layer was separated and washed with brine, dried over anhydrous MgSO 4 , and evaporated under reduced pressure. The obtained residue was puried using column chromatography on silica gel to obtain the pure product. The yield was 75-92%.

Conclusions
In conclusion, we have successfully established an efficient route toward the synthesis of a diverse array of pyridinecontaining pseudopeptide backbone derivatives in the presence of a novel nano-catalyst through the design of an expedient post-transformation reaction sequence. This approach was efficient, facile, cost-effective, highly diverse, and high-yielding. We obtained products from readily available starting materials. Also, a new copper complex supported on MCM-41 was synthesized and fully characterized using different methods. The design of novel cyclization reactions using 1,5-enynes in the presence of novel catalysts is in progress in our laboratory.

Conflicts of interest
There are no conicts to declare.