Copper Immobilization on Fe3o4@Agar: An Ecient Superparamagnetic Nanocatalyst for Green Buchwald-Hartwig Cross-coupling Reaction of Primary and Secondary Amines With Aryl Iodide Derivatives

Immobility of copper on magnetic nanoparticles was performed using surface rectication of Fe 3 O 4 with Agar. The magnetic Fe 3 O 4 @Agar-Cu nanocatalyst was prepared and entirely characterized by different analyses such as Fourier transform infrared (FT ‐ IR), X ‐ ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), vibrating sample magnetometry (VSM), energy dispersive X-ray (EDX), thermogravimetric (TGA), and inductively coupled plasma (ICP). The nanocatalyst was applied in C-N bond formation through the cross-coupling reaction of aryl halides with primary or secondary amines in water as a green medium known as the Buchwald-Hartwig reaction. The results of the Buchwald-Hartwig reaction by Fe 3 O 4 @Agar-Cu magnetic nanoparticles as catalyst demonstrate excellent activity and stability in water. Moreover, this catalyst can be recycled several times without considerable loss in its activity.


Introduction
In recent decades, the lack of green processes in the chemical elds and industries is a signi cant concern. Green Chemistry is effective for human health and necessary to protect the environment. [1,2] Concern of pollutions, toxicity, and waste treatment methods are an essential issue for all chemists to use neat solvents, especially water, in their chemical processes because of the availability, recyclability, thermal stability and chemical conditions. [3][4][5] There is lots of investigation to nd a better catalyst, ligand, base, or more effective solvents for the Buchwald-Hartwig reaction known as C-N cross-coupling. Considering an in uential catalyst that can be utilized for both primary and secondary amines and act as a regiospeci c catalysts in satisfying yields have been investigating very much.[6-10] The Buchwald-Hartwig is an essential reaction since aryl amines are commonly used in pharmaceutical treat, materials, and drugs with interesting electronic properties. [11] Neratinib was approved in 2017 for the expanded attendant treatment of positive breast cancer ( Fig. 1-I). Abemaciclib as a cyclin-dependent kinase inhibitor, is used for the treatment of breast cancer. Pd 2 (dba) 3 can catalyze the Buchwald-Hartwig reaction to achieve the Abemaciclib drug ( Fig. 1-II). [12] Recently, the use of catalysts in many forms is a primary topic in Organic chemistry. Especially, using magnetite as one of the best support surfaces is guaranteed some properties such as the control of unwanted reactions, the stability of PH, the simplicity of the separation method and reusing of the catalyst several times, high surface area and low toxicity. [13][14][15][16][17][18][19] The rst catalyst that represented for Buchwald-Hartwig reaction was the Pd metal complex by organic or inorganic ligands that were accepted as the best catalyst in recent years. [20][21][22] Stephen L. Buchwald and coworkers reported e cient catalysts for the catalytic amination of a wide variety of aryl halides and tri ates in 2000. [23] The palladium-catalyzed amination of aryl halides had been successfully known as an important method for the Buchwald-Hartwig C-N cross-coupling reaction. A variety of catalysts represented for this reaction such as (Fe 3 O 4 @PDA/Pd(II) ) [24], (Zn(OAc) 2 ) [25], (NiCl(bpy)(IPr))[26]. There are still limitations in some processes a liated with transition metal, speci cally using Pd [27][28][29][30][31][32][33], for example, using these high-cost metals and the di cult process in the workup. [34] In the study of the reaction, Cu is one of the most incredible noble element that can be replaced by Pd metal. Agar as a plentiful, non-toxic, cheap, and natural biopolymer, is considered as a linker for this kind of catalyst. [35][36][37][38][39][40][41] It can be found in the cell wall of some red algae and its strong gelling seaweed hydrocolloid composed [42]. Hitherto, the main structure of Agar-Agar is chemically characterized by the repeating units of d-galactose and 3,6-anhydro-l-galactose. Also, it has a chiral surface with free hydroxyl groups that could act as hydrogen bond donors or acceptors. [41,43] Based on the above information and our previous studies [22,44- SEM imaging of the nanoparticles shows nanometer-sized particles of less than 25 nm in diameter. Fig. 4 shows the morphology of the Fe 3 O 4 @Agar-Cu nanoparticles with a core-shell structure and spherical form.
TEM image of the catalyst has been shown in Fig. 5. The spherical shape of each nanoparticle corresponded to the core of the catalyst, similar to SEM image which can be observed at a scale of less than 25 nm. Also, TEM images show that magnetic nanoparticles of Fe 3 O 4 have been encapsulated by the biopolymeric network of Agar.
The magnetization curve displays that the Fe 3 O 4 @Agar-Cu NPs have paramagnetic attributes in which the nanoparticles can be easily separated from the reaction melange using an external magnet.
To specify the elemental composition of Fe 3 O 4 @Agar-Cu NPs, EDX analysis was ful lled (Fig. 7). The

Catalytic application of Fe 3 O 4 @Agar-Cu catalyst
After the characterization of the catalyst structure, the new prepared catalyst e ciency has been investigated in the Buchwald-Hartwig reaction. Initially, in order to optimize the model reaction conditions of iodobenzene with aniline, some parameters, including solvents, amounts of catalyst, temperature and the time of reaction were scrutinized thoroughly. (Table 1) The impact of the catalyst was inspected with different amounts of Fe 3 O 4 @Agar-Cu. The reaction did not proceed in the absence of the catalyst even after 15 h. The effect of solvents was also examined by polar and nonpolar solvents, including DMSO, DMF, Toluene and water. Fortunately, a high yield was observed in H 2 O as a green and sustainable solvent. The effect of time duration and temperature on the model reaction was also evaluated, and it was found the best time and temperature are considered as 12 h in 100 ºC with excellent yield.
Next, in order to expand the scope of this reaction, various derivatives of C-N bond cross-coupling reactions have been represented in Table 2. Considering both primary and secondary arylamines was the wisdom of this catalyst that is not previously usual. There are not any signi cant differences in reaction yields considering various amines (primary or secondary) bearing electron-donating or electron-with drawing groups, and all related products were obtained in good to excellent yields. Also, for improving the validity of the synthesis eld and larger scale of the reaction, coumarins (entry 16 and 17) were considered as complicated amine structures. They were conducted in Buchwald-Hartwig amination reaction using Fe 3 O 4 @Agar-Cu NPs as the catalyst. The results showed magni cent success and remarkable yields based on con rmation by Mass spectroscopy, 1 H, and 13 C NMR analyses.
As it is presented in Table 3, the comparison of this catalyst with some recently published catalysts has been performed. Various conditions have been applied, but the use of green and nontoxic reaction conditions has not been reported. Employing reachable and no harmful materials, achieving high yields of product, and mild reaction condition is the art of this study.
To check the catalyst's reusability on the model reaction, the nanocatalyst was removed easily from the mixture after the termination of the reaction, washed with ethanol and deionized water successively, and dried in vacuum oven. Soon afterward, the catalyst applied directly for the next run. Providentially, this catalyst was reused for ve times and shown good revenue in the reaction process by the use of ICP analyses without signi cant leaching of Cu NPs (Fig. 9).
The possible mechanism of C-N cross-coupling represents in Fig. 10. The proceed mechanism is the same as C-C cross-coupling reactions. [13] Including oxidative addition of the aryl halide to a Cu 0 nanoparticle, the addition of the amine to the oxidative addition complex, deprotonation followed by reductive elimination of the species intermediate releases the desired product amines and complete the reaction cycles. 3.2. Synthesis of copper nanoparticles coated magnetic Agar: Fe 3 O 4 @Agar-Cu NPs Fe 3 O 4 @Agar (0.8 g) was dispersed in deionized water (80 ml) in an ultrasonic bath for 15 min. Then, an aqueous solution of CuCl 2 (50 g/lit) is added dropwise over, for 15 min at room temperature. The mixture is mechanically stirred for the other 3 h. Subsequently, NaBH 4 (500 mg) is gently added to the mixture and stirred for 4 h. The color of the solution is changed from colorless to dark brown during the reaction. Eventually, Fe 3 O 4 @Agar-Cu NPs are separated by an external magnet, washed several times with water, and dried in a vacuum desiccator at room temperature.

General procedure for C-N cross-coupling reactions
To a mixture of primary amine or secondary amine derivative (1 mmol) and the appropriate aryl iodide (1.1 mmol) in water (0.5 ml for primary amines and 4 ml for secondary amines) and K 2 CO 3 (1 mmol for primary amines and 2 mmol for secondary amines), Fe 3 O 4 @Agar-Cu NPs (10 mol%) was added, and the mixture is re uxed at 100 ºC for 12 h. The progress of the reaction was monitored by TLC. After completing the reaction, the catalyst was separated using an external magnet, and the crude product is extracted from the aqueous phase by EtOAc. Finally, the pure products were isolated using column chromatography on silica gel using n-hexane/EtOAc as eluent.

Conclusion
In conclusion, we have demonstrated a noble, stable, versatile, and unique catalyst named Fe 3 O 4 @Agar-Cu NPs replaced for speci c Buchwald-Hartwig catalyst reaction that usually used expensive and inaccessible Pd metal. Considering Agar as a pure and natural linker and also water as an eco-friendly solvent made this reaction undoubtedly a Green process. There is no harsh condition and surpass than the old method. More importantly, this catalyst effort both primary and secondary amines with signi cant yields that represent various derivatives. Figure 1 Examples of Buchwald-Hartwig reaction in dugs treatment      Energy-dispersive X-ray spectroscopy for Fe3O4@Agar-Cu NPs.  Reusability of the catalyst for the model reaction.

Figure 10
The possible mechanism for cross-coupling Buchwald-Hartwig reaction in the presence of Fe3O4@Agar-Cu nanoparticles.