Copper (II)-immobilized on Starch-coated Nanomagnetite as an Efficient and Magnetically Recoverable Catalyst for the Synthesis of Propargylamines through One-pot A3 Coupling Reaction

Propargylamines are considered as essential building blocks for the synthesis of numerous biologically active compounds and natural products including b -lactams, peptides, and oxotremorine analogues. 1 From the pharmaceutical and therapeutic aspects, propargylamine moieties exhibit considerable activity as enzyme inhibitory, 2 anti-HIV, 3 anti-cancer, 4 antibiotic, 5 anti-Parkinson, 6 anti-Alzheimer 7 and anti-apoptotic 8 agents. Moreover, they can act impressively as synthetically fruitful intermediates to construct N -heterocyclic compounds, including quinolones, 9 oxazoles, 10 pyrroles, 11 pyrrolidines, 12 indolizines 13 and oxazolidinones. 14,15 Owing to the importance and utility of propargylamines, several methods have been reported for their preparation. In this regard, trad-itional protocols comprise direct amination of propargylic halides, propargylic phosphonates, or propargylic triflates, 16 as well as the nucleophilic addition of metal acetylide reagents to imines or enamines. 17 However, these procedures suffer from some fundamental obstacles; these may be problematic workup procedures with the produc-tion of large amounts of waste, low atom economy and utilization of stoichiometric quantities of moisture-sensitive reagents. Taking into account these crucial limitations, three-component coupling (so-called “ A 3 coupling ” ) through Mannich condensation of terminal alkynes, aldehydes, and amines has been offered as the most prominent and efficacious method for achieving the corresponding propargylamines in an environmen-tally

and reusability of the catalyst. The immobilization of homogeneous catalysts onto solid supports can merge the advantages of homogeneous catalysts with simple separation and retrieving features of heterogeneous catalytic systems. 29 Thus, design and development of desirable and well organized heterogeneous catalysts for A 3 coupling has attracted growing attention in recent years. 30 In this trend, nanocatalysts -and particularly nanomagnetic catalysts -play an important role. 31 Among the magnetically recoverable entities, Fe 3 O 4 magnetic nanoparticles with remarkable surface area, outstanding thermal and chemical stability and easy surface functionalization have been widely applied. Heterogeneous catalysts on surface functionalized Fe 3 O 4 nanoparticles have thus found numerous applications in organic synthesis. [32][33][34][35] Accordingly, several reports have been presented to utilize nanomagnetic copper-based catalysts for the preparation of propargylamine derivatives. [36][37][38][39][40][41][42][43] Immobilization of metal ions onto the surface of natural polymers, such as polysaccharides, could be the basis of an appropriate heterogeneous catalytic system for organic transformations. 44,45 As a notable example, starch is a ubiquitous, biodegradable, renewable, non-toxic, and low-cost material which can be conveniently functionalized and modified. It has been broadly employed in various fields including the pharmaceutical, textile and food industries. 46,47 In addition, functionalized starch is suitable as an adsorbent 48,49 and catalyst support. [50][51][52] In this context, a few approaches have been reported on the utilization of nanocatalysts containing copper ion immobilized on modified starch to catalyze the A 3 coupling reaction. 53,54 In continuation of our attempt to design and employ nanomagnetic catalysts for promoting the A 3 coupling reaction, 55,56 we now report the synthesis of immobilized copper (II) on starch/polyacrylate-modified nanomagnetite (Fe 3 O 4 @Starch-Acr@Cu(II)) as an effective and magnetically retrievable catalyst for the synthesis of propargylamines through the onepot three-component reaction of terminal alkynes, aldehydes, and amines (Scheme 1).
In order to determine the optimized reaction conditions for preparation of propargylamine derivatives, the reaction of 4-chlorobenzaldehyde, phenylacetylene and piperidine was applied as a model reaction. Initially, different catalysts were examined to select the most effective one for our model reaction ( catalyst, and 0.025 g of the catalyst was determined as a sufficient amount (Table 1, entries 4-6). In this case, utilization of higher amount (0.030 g) did not influence the yield of the reaction (Table 1, entry 6). It is noteworthy that no product formation was observed after 24 h in the absence of the catalyst (Table 1, entry 9).
In the next step, to survey the effect of solvent on the progress of our model reaction, several solvents including N,N-dimethylformamide, ethanol, toluene, acetonitrile, tetrahydrofuran and water were examined ( Table 2, entries 1-6). Furthermore, the model reaction was carried out under solvent-free conditions (Table 2, entry 7). As shown in Table 2, water afforded the highest yield of the product. To evaluate the optimum temperature, the progress of the model reaction was screened at room temperature, 70 C, 90 C and 100 C (reflux temperature), and 100 C was determined as the proper temperature for the reaction (Table 2, entries 6, 8-10). For further investigation of the optimum conditions, the best molar ratio of the substrates was also inspected ( Table 2, entries 6,[11][12][13]. In this regard, various molar ratios of reactants were explored; the molar ratio 1:1.2:1.5 (aldehyde:amine:alkyne) was attained as the appropriate ratio.
Utilizing the optimized reaction conditions, aromatic aldehydes containing electrondonating and electron-withdrawing groups, together with aliphatic and heterocyclic aldehydes, were applied for the synthesis of propargylamines through the one-pot A 3 coupling reaction. Amine components included piperidine, morpholine and pyrrole. As can be seen in Table 3, in most cases the three component reaction successfully proceeded to give the corresponding propargylamine in very good yields (mean 87%) and short reaction times. According to the results, both electron-deficient and electron-rich aromatic aldehydes (Table 3, entries 2-11), as well as aliphatic aldehydes (Table 3, entries 12-13) were converted into the propargylamine products through reaction with piperidine and phenylacetylene. Heterocyclic aldehydes ( Table 3, entries 14-17), especially furfural and thiophene-2-carboxaldehyde, also exhibited favorable reactivity under the same conditions. In a similar way (by using 2 mmol of piperidine and phenylacetylene), terephthaldehyde was transformed into the related propargylamine (Table 3, entry 18). Utilization of other secondary amines such as morpholine (Table 3, entries 14-17) and pyrrole (Table 3, entry 18) showed variations in product yield and reaction time. However, employing a primary amine, i.e. aniline, for coupling with 4-chlorobenzaldehyde and phenylacetylene made no progress after 24 h, due to the formation of a stable imine intermediate (Table 3, entry 23). When using a ketone instead of an aldehyde ( Table 3, entry 24), or substituting for phenylacetylene with propargyl bromide or 1ethynylcyclohexanol (Table 3, entries 25-26), no A 3 coupling reaction was observed even after 24 h. Evaluating the effect of ortho, meta and para substituents demonstrated no evident preference for any of these positions for o, m and p-bromobenzaldehyde (Table 3, entries 3-5). Nevertheless, in the case of ortho and meta-hydroxybenzaldehyde, a remarkable priority was seen for the meta position (Table 3, entries 10-11). This may be ascribed to the formation of hydrogen bonds between the hydroxyl group and the carbonyl oxygen of ortho-hydroxybenzaldehyde, which may block the carbonyl from effective paticipation in the A 3 -coupling reaction. The ability to recover and reuse the catalyst is a critical parameter in the assessment of the efficiency of heterogeneous catalysis. The reusability and recovery features of Fe 3 O 4 @Starch-Acr@Cu(II) were evaluated in our model reaction. The catalyst was separated after completion of the reaction (see Experimental section) and was reused. Due to the magnetic behavior of the catalyst, it was easily retrieved from the reaction medium using an external magnet and subsequently was washed several times with acetone. After being dried in a vacuum oven at 70 C, it was utilized for the next run. Our nanocatalyst could be recovered and reused up to 5 times with negligible decline in its activity with regard to the fresh catalyst (Fig. 1). It is noteworthy that the SEM and IR analysis of the reused catalyst did not reveal significant changes after being used five times (see Supplementary Materials).
Beyond the results seen in Table 1, further insight about the catalytic utility of Fe 3 O 4 @Starch-Acr@Cu(II) was achieved through a comparison with other catalytic systems of current interest, and the results are summarized in Table 4. As shown in Table     In summary, we have presented a convenient, fast and eco-friendly protocol for the synthesis of propargylamine derivatives via one-pot three-coupling reaction of phenylacetylene, amines and aldehydes by employing Fe 3 O 4 @Starch-Acr@Cu(II) as an efficient magnetically retrievable and reusable catalyst. By using this protocol, a diverse range of propargylamine products were obtained in short reaction times and remarkable yields. The nanomagnetic catalyst was readily recovered from reaction mixture via an external magnet and was utilized several times with only a slight decrease in its catalytic effect.

Experimental section
Starch, N,N-methylenebis(acrylamide) (MBA), ammonium persulfate (APS), ferric chloride hexahydrate (FeCl 3 Á6H 2 O), aqueous ammonia (25%) and ferrous chloride tetrahydrate (FeCl 2 Á4H 2 O) were purchased from Fluka and Merck companies and used without further purification. Acrylic acid (AA, supplied from Merck Company) was utilized after purification by vacuum distillation. Other materials and solvents were purchased from Merck Company and used as received. Melting points were measured by means of an Electrothermal Engineering IA9100 apparatus and are uncorrected. 1 H and 13 C NMR spectra were obtained using a Bruker Avance III 400 MHz spectrometer. The X-ray powder diffraction (XRD) pattern of the catalyst was obtained using a Philips PW 1830 X-ray diffractometer with CuKa source (k ¼ 1.5418 Å) in a range of Bragg's angle (10 -80 ) at room temperature. Scanning electron microscope (SEM) images were taken by use of a VEGA//TESCAN KYKY-EM3200 microscope (acceleration voltage 26 kV). Thermogravimetric analysis (TGA) was carried out on a DuPont 951 Analyzer with the heat rate of 10 C/min under N 2 atmosphere. CHN analysis was performed via a CHN

Preparation of Fe 3 O 4 @Starch-Acr
In the next step, modification of the nanomagnetite with starch and polyacrylate was accomplished. According to the literature, 67 in a two-neck round bottom flask equipped with mechanical stirrer, a suspension of starch (1 g) in deionized water (60 mL) was heated in a water bath at 70 C for 2h. Upon dissolving the starch and formation of a homogenized solution, Fe 3 O 4 nanoparticles (1 g) were added and the solution was subjected to sonication for 10 min. Next, acrylic acid (30% neutralized using sodium hydroxide; 3 g), N,N-methylenebis(acrylamide) (0.5 g) and ammonium persulfate (0.1 g, as polymerization initiator) were concurrently added and then the reaction mixture was allowed to stir for a further 15 min. After observing gel formation and completion of the polymerization, the reaction mixture was cooled to room temperature. Afterwards, to remove the water from the product, ethanol (400 mL) was added to the gelled nanocomposite and the resultant was allowed to stand for 48 h. Subsequently, the attained nanoparticles were filtered, washed with fresh ethanol and dried in a vacuum oven at 50 •C for 12 h, giving the product (6 g) as a brown precipitate.

Synthesis of Fe 3 O 4 @Starch-Acr@Cu(II)
To prepare Fe 3 O 4 @Starch-Acr@Cu(II), the immobilization of Cu(II) ions onto the Fe 3 O 4 @Starch was carried out through the following process: Fe 3 O 4 @Starch (0.5 g) was added to a solution containing CuSO 4 Á5H 2 O (1.6 g) in deionized water (10 mL) and then the mixture was stirred at 75 C for 24 h. After completion of the reaction, the precipitate was collected by an external magnet, washed with deionized water (20 mL) and dried in vacuum oven at 70 C for 12 h to afford the Fe 3 O 4 @Starch-Acr@Cu(II) (0.4 g) as a green solid. The synthesized catalyst was well characterized by TGA, VSM, CHN, XRD, SEM, IR, ICP and EDX analyses, the results of which are available in the Supplementary Materials or from the corresponding author upon request.

General procedure for the synthesis of propargylamines
In a 25 mL two-neck round bottom flask equipped with mechanical stirrer, a mixture of the appropriate aldehyde (1 mmol), amine (1.2 mmol), alkyne (1.5 mmol) and Fe 3 O 4 @Starch-Acr@Cu(II) (0.025 g) in H 2 O (1.5 mL) was allowed to stir under reflux conditions. The progress of the reaction was monitored by thin-layer chromatography (TLC, silica gel, n-hexane:ethylacetate 9:1). After completion of the reaction, the catalyst was separated using an external magnet. Then, ethyl acetate (10 mL) was added to the resulting mixture. After separation of the organic phase, it was dried over MgSO 4 , filtered, evaporated under reduced pressure and, if needed, the desired product was isolated by silica gel column chromatography (n-hexane:ethyl acetate (9:1)). All of the organic products of this study were known materials, identified on the basis of comparison of their characteristics with those in the literature references cited in the individual preparations.