Alkyl ammonium hydrogen sulfate immobilized on Fe3O4@SiO2 nanoparticles: a highly efficient catalyst for the multi-component preparation of novel tetrazolo[1,5-a]pyrimidine-6-carboxamide derivatives

In this, a three-component reaction for the preparation of novel tetrazolo[1,5-a]pyrimidine-6-carboxamide derivatives from N,N′-(sulfonylbis(1,4-phenylene))bis(3-oxobutanamide), aldehydes and 1H-tetrazol-5-amine is reported. The application of Fe3O4@SiO2-(PP)(HSO4)2 (A) as a catalyst afforded the desired products (a1–a18) in high yields in DMF as solvent as well as under solvent-free conditions.


Materials and methods
The complete procedures, material characterization, and instruments can be found in the supplementary data file attached to this paper.
Fe 3 O 4 and Fe 3 O 4 @SiO 2 nanoparticles were prepared according to our previous work 22,27 General procedure Method 1 In a 50 mL balloon equipped with a condenser, N,N'-(sulfonylbis(1,4-phenylene))bis(3-oxobutanamide) (1 mmol), 1H-tetrazol-5-amine (2 mmol), and benzaldehyde (2 mmol), and A (0.025g, 0.05 mmol H + ) were mixed in DMF (20 mL) and the mixture was mechanically stirred at 100 °C under ultrasonic irradiation for the time depicted in Table 2.After the reaction was completed (TLC following), the solvent was evaporated under reduced pressure and the solid was recrystallized from ethanol to afford the desired products.

Cl
To further characterize Fe 3 O 4 @SiO 2 -(PP)(HSO 4 ) 2 (A), the samples were subjected to XRD analysis to determine the crystalline phases.Figure 3   shoulder located in the 10-30 (2Ɵ°) range, which may be due to the amorphous phase of silica.Furthermore, the peaks related to the Fe 3 O 4 phase have lower intensities due to the integration of organic parts and the SiO 2 phase.
Next, the thermal behavior of (A) was investigated by TGA-DTA analysis (Fig. 5).The sample is stable up to 200 °C and shows four different mass losses due to the removal of the adsorbed water (50-200 °C), removal of SO X gases (200-320 °C), decomposition of the organic part by the removal of CO 2 , H 2 O, and NOx gases  (300-550 °C), and the formation of SiO 2 phase (500-800 °C). 45Accordingly, the ratio of inorganic to organic parts is nearly 2/1, which is close to the ratio of the initial substrates.

Determination of active sites
The sample has an acidic nature and thus, the determination of H + values is important to investigate the role and determine the conditions for the application of the sample as a catalyst.The values of H + were determined by EDX analysis, TGA method, and barium sulfate (BaSO 4 ) titration-precipitation test.The obtained results are shown in Table 1.
The sulfur values of the sample were determined through the sulfur element percent in the results of EDX analysis (S, 6.89%).Similarly, the amount of S atoms could be determined by the values of SO x removal using TGA.The BaSO 4 method involves titration by barium chloride solution.Accordingly, the H + capacities of the sample were found to be 2.15, 2.71, and 2.03 mmol H + /g by EDX, TGA, and BaSO 4 tests, respectively.
To assure the desirable performance and facile separation of the nano-catalyst, by a magnetic field, VSM analysis was used.Figure 6 shows the plotted results of VSM analysis performed at 25°C within the magnetic field of − 10,000 to 10,000 Oe.According to the hysteresis curves shown in Fig. 6, the functionalization of the Fe 3 O 4 decreased the VSM characteristic values including saturation magnetization (M s ), remanence magnetization (M r ), and coercivity field (H c ) (Table 2).However, Fe 3 O 4 exhibited a considerable magnetic nature.
In organic-inorganic hybrids, such as those used here, the organic part hurts the saturation magnetization.The organic chain has a diamagnetic effect and accordingly, the sample (A) shows lower magnetic saturation than Fe 3 O 4 and Fe 3 O 4 @SiO 2 samples.In addition, our observations confirm the easy recovery of the catalyst by an external magnet.

Reaction condition optimization
The prepared sample (A) was then used in the synthesis of tetrazolo[1,5-a]pyrimidine-6-carboxamide derivatives to act as a catalyst.Initially, the reaction of N,N'-(sulfonylbis(1,4-phenylene))bis(3-oxobutanamide), 1H-tetrazol-5-amine, and benzaldehyde was chosen as a model for the synthesis of 5-methyl-N-(4-((4-(5-methyl-7-phenyl-4,5,6,7-tetrahydrotetrazolo[1,5-a]pyrimidine-6-carboxamido)phenyl)sulfonyl)phenyl)-7-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide (a 1 ).To determine the optimal conditions in the synthesis of compound (a 1 ), the model reaction was studied using different solvents, catalyst dosages, and temperatures (Table 3).According to the results obtained, the reaction did not proceed at low temperatures.In addition, nonpolar, less polar, and polar solvents with boiling point less than 100°C such as hexane, dichloromethane (CH 2 Cl 2 ),  chloroform (CHCl 3 ), and ethyl acetate (EtOAc) were not suitable for the reaction.In aqueous media, no products were formed.Upon increasing the reaction temperature up to 100 °C, the reaction yields in tetrahydrofuran (THF) and toluene were 56 and 20%, respectively.Notably, the reaction had an acceptable yield in dimethyl formamide (DMF, 79%).To obtain better product yields, ultrasonic irradiation (US) was used.A high product yield (95%) was obtained under ultrasonic irradiation using DMF solvent.Notably, under solvent-free conditions and ultrasonic irradiation, the desired product (a 1 ) was formed in a high yield (91%) at 100 °C.Next, the reaction was investigated using different dosages of the catalyst.In the absence of the catalyst, no product was formed.The results revealed that 0.5 g of the catalyst gave the highest yield of the product (a 1 ).Thus,   www.nature.com/scientificreports/DMF solvent and solvent-free conditions were selected as the two best media for the reaction while the suitable catalyst dosage was determined as 0.05 g, as it provided the highest yields at reasonable reaction times (Table 3).Under the optimized conditions, the scope of the reaction was expanded using various aromatic and aliphatic aldehydes.The results are shown in Table 3. Accordingly, when aliphatic aldehydes were used, no product was formed.However, different aromatic aldehydes were found to be appropriate substrates in the reaction.The electronic effects of the substituents on the aromatic ring in the aromatic aldehydes are expected to affect the reaction rate.Based on the results obtained, electron-donating substituents increased the reaction rate, contrary to electron-withdrawing groups (Table 4).
Scheme 3 shows a plausible proposed reaction mechanism for the synthesis of compounds a 1 -a 18 .As suggested, the Brønsted acid catalyst activates the carbonyl groups.The reaction starts with the reaction of NH 2 group with the activated carbonyl groups to form an enamine active compound (Intermediate I 1 ).The next step is the reaction of I 1 with the activated aldehyde to form I 2 .Intermediate I 2 undergoes cyclization and enamine formation to yield the final products.Finally, an external magnet could be used to recover the catalyst, which was then washed with ethanol, dried, and used again.The preparation of (a 1 ) was chosen for the recovery test.The recovery experiments showed acceptable results after 10 catalytic runs (Fig. 7).The XRD pattern of the recovered catalyst confirmed the stability of the catalyst during the reaction (Fig. 1).In addition, after each run, the recovered catalyst was tested using titration by barium chloride solution.The results indicated good catalyst stability and no clear leaching was observed.

Conclusion
In this work, tetrazolo[1,5-a]pyrimidine-6-carboxamide derivatives were prepared using Fe 3 O 4 @SiO 2 -(PP) (HSO 4 ) 2 (A) as a catalyst.The TGA-DTA analysis indicated the stability of this organic-inorganic hybrid up to 200 °C.In addition, the ratio of the inorganic to organic parts was 2/1, which was close to that of the initial substrates.Using the barium chloride titration test, the H + capacity of the sample was determined to be 2.03 mmol H + /g.The XRD pattern of the fresh and recovered samples (A) confirmed the stability of the catalyst.The results showed promising potential and easy recovery of magnetic nano-catalysts.The obtaining of reasonably high yields in short reaction times and readily available starting materials make this protocol potentially useful in organic synthesis.

Figure 7 .
Figure 7. Recovery of A (Methods 1,2) and leaching test results in the synthesis of (a 1 ).

Table 3 .
Optimization of the reaction conditions.*Isolated Yield; based on the preparation of a 1 .