The Q-Tube-Assisted Green Sustainable Synthesis of Fused Azines: New Synthetic Opportunities via Innovative Green Technology

Abstract

An efficient, economical, and green, sustainable synthesis of fused azines using Mg-Al hydrotalcite under a high-pressure Q-Tube reactor has been developed. This reaction proceeds through the aza-Michael addition of α,β-unsaturated ketone with different aminoazoles. This method offered excellent yields in a short reaction time that economically saved energy in addition to the protocol showing the reuse of the catalyst seven times without losing its catalytic activity.

1. Introduction

Two different scientific areas, chemistry, and economy are affected by environmental challenges and develop in divergent ways. To deal with complex environmental problems, a green economy and green chemistry were released, which collaborate by sharing knowledge and supporting each other. Environmental, ecological, and sustainable challenges can be addressed through green chemistry. Nowadays, the role of green chemistry has become crucial, which serves the green economy via collaborative efforts to solve environmental challenges toward sustainability. As energy consumption rises globally, fossil fuels continue to play a major role [1,2]. The golden rule in green chemistry continues to optimize energy intensity while minimizing energy consumption during chemical processes with repercussions that extend beyond the scope of chemists: 95% of manufactured goods involve a chemical process as part of their production process [3]. According to recent research, any green business based on green chemistry is considered part of the green economy [4]. Although the utilization of microwaves in organic synthesis is considered one of the important green chemistry tools that save energy in fine chemical synthesis [5], several drawbacks associated with this tool, such as the high cost of microwave apparatus in comparison with conventional synthesis tools (oil-bath, or hot plates), and the scale-up of microwave-mediated synthesis has yet to reach the production levels of conventional synthesis [6]. Recently, a novel green chemistry tool was released, which is known as the Q-tube pressure system. High-pressure chemistry can be performed using this inexpensive and simple tool instead of expensive microwave synthesizers (Figure 1) [7].

To prevent overpressure explosions, the Q-Tube incorporates a pressure release and resealing mechanism [8]. In addition, the efficiency and yield of reactions performed in Q-Tube reactors are higher than those of MW reactors at high pressure [9]. The Q-Tube enhances the organic reaction by influencing two factors. The first one is that the solvent’s boiling point is exceeded during the reaction process. The Arrhenius equation states that reaction rates double when the temperature is raised by 10 °C (Equation (1)).

$$\mathrm{K}=A{e}^{-E_a/RT}$$

(1)

E_a is an activation energy, and K is a rate constant for gas. R is the gas constant for gas (8.3145 J/Kmol). Temperature is defined as T. Reaction frequency and molecular orientation are used to calculate a frequency factor of A [10,11]. The second factor is that, due to high pressure in the Q-Tube system, the reaction volume reduces, including liquids that result in faster reactions as a result of collision frequency increasing. Safety, accuracy, and high reproducibility are guaranteed with the Q-Tube^™ system. Figure 2 illustrates the design as a Qian cap with a Teflon septum and needle for active ventilation (which avoids rapid pressure increases).

On the other hand, for a plethora of organic reactions, layered double hydroxides [LDHs] can serve as catalysts [12,13,14,15]. The hydroxyl groups in Mg(OH)₂ [brucite] coordinate octahedrally with some Mg²⁺ cations, similar to that in brucite, whereas some Al³⁺ ions are substituted with trivalent ions. LDH layers have an excess of positive charges, which are compensated by anions and water in interlayer spaces. During synthesis, cations in the octahedral sheet can vary, and different compensating anions introduced in interlayer regions can tailor the surface properties of minerals. Therefore, we previously succeeded in studying the catalytic activity of Mg-Al-Hydrotalcite (Mg-Al-HT) in its as-synthesized form in the aza-Michael addition reaction [16]; this exhibited a superior catalytic activity as we obtained the highest yield in the shortest reaction time in comparison with the thermally activated one [16].

Bearing in mind all of the above and inspired by our previous work utilizing green chemistry tools for the synthesis of biologically active heterocyclic compounds [17,18,19,20] and the recently published work on utilizing the high-pressure Q-tube [21,22,23,24,25], we are encouraged to highlight and confirm the success of the Q-tube system in organic synthesis as economic tools that save energy. In this study, we tested the Q-tube for the reaction of chalcones with nitrogen nucleophils.

2. Results and Discussion

First, the behavior of chalcone 1 toward aminopyrazole derivative 2a, which may serve as a precursor to bioactive pyrazolo[1,5-a]pyrimidine derivatives, was scrutinized utilizing the Q-Tube system. Initially, a group of solid basic catalysts were tested for the mentioned aza Michael addition reaction (Scheme 1). The solid basic catalysts used in the reaction depicted in Scheme 1 are named potassium carbonate, basic alumina, KF-Basic alumina, and Mg-Al-Hydrotalcite (Mg-Al-HT) (

Table 1. Optimization of the reaction condition for the synthesis of fused pyrimidines.

Entry	Catalyst	(Reflux) *		MW **		Q-Tube **
		Yield	Time	Yield	Time	Yield	Time
1	None	0	12 h	0	50 min	0	50 min
2	K2CO3	58%	12 h	75%	40 min	75%	40 min
3	Basic alumina	61%	9 h	84%	30 min	82%	35 min
4	KF/basic alumina	68%	7 h	88%	30 min	85%	30 min
5	Mg-Al HT	77%	6 h	96%	12 min	95%	10 min

* Equimolar amounts of reactants in ethanol at 70 °C, ** Equimolar amounts of reactants at 100 °C.

). These choices are based on a high degree of reusability and low environmental impact.

Table 1 shows that when utilizing the Q-tube system, the excellent yield and shortest reaction time was attained via Mg Al-HT (95%, 10 min. entry 5). Also, KF-basic alumina and basic alumina itself provided good results (entry 3 and entry 4), but the lowest yield were attained with potassium carbonate (entry 2). In all cases, only one isolable product was obtained, as examined by TLC. To address the beneficiary effect of the Q-tube system on the above-mentioned reaction, all the above experiments (Table 1) were compared with conventional heating and microwave irradiation (Table 1). Both the Q-tube system and microwave reactor exerted pressure on the reaction, and their results were almost similar, though the Q-tube is still the best because it is economical and easier than the microwave reactor. Also, Table 1 proves that the Q-tube system reduced the reaction time from 6 h under conventional conditions to 10 min and increased the reaction yield from 77% yield under conventional conditions to 95% yield. The superiority of Mg Al-HT as a solid basic catalyst is in line with our previous results for the aza-Michael addition reaction [16]. An explanation for the outstanding effect of the Q-tube is based on the fact that chemical reactions are forced via the acceleration of transitions between liquids, solids, and gases. Pressure effects can be explained by the effect on reaction volume and activation volume [26]. A high-pressure chemistry process can improve the physical properties of solvents, reagents, and final products, achieving cleaner and faster transformations. The physical properties of liquids are the most modified. When pressure is increased, vapor pressure directly correlates with solvent boiling points [27,28,29]. According to the Arrhenius equation, the reaction rate can double with every 10 °C increase in temperature [30]. Scheme 1 shows the formation of aza-Michael addition adducts that could be converted into a product and formulated as 3a, 4a, or its isomer 5a. The ¹H and ¹³C NMR spectra of products obtained from the reaction proved the presence of a (-CH₂-CH-) building block and ruled out an NH function that is consistent with structures for 3a or its isomer 5a. However, structure 3a appears to be more likely based on the spectral data and similarities to the known behavior of α,β-unsaturated carbonyls toward amino pyrazole [31,32,33] in which the addition of ring nitrogen to the activated bond system is assumed to be the first step followed by the elimination of one water molecule, as depicted in Scheme 1, to afford the corresponding 7-(4-fluorophenyl)-5-(furan-2-yl)-2-phenyl-6,7-dihydropyrazolo[1,5-a]pyrimidine (3a) in an almost quantitative yield. Furthermore, ¹H-¹H NOESY 2D spectrum measurements for the isolated compound revealed the neighborhood of the methine proton and the ortho protons of the 4-fluoro phenyl group (Figure 3). The latter result excluded isomer 5a. The structures of 3a are in agreement with spectral data of the reaction product. For example, the IR spectrum of compound 3a showed a C=N band at 1601 cm⁻¹. The ¹HNMR analysis of the same compound exhibited two dd signals at δ 3.42 and 3.50 ppm due to Ha and Hb, respectively, and another dd signal at δ 5.67 ppm due to the Hx proton in addition to a singlet signal at δ 6.76 ppm corresponding to pyrazole H-3 and aromatic protons and furan protons as the multiplet at δ 6.95–7.82 ppm. (cf. experimental part).

A range of aminopyrazole derivatives 2b,c were tested under optimized conditions (Scheme 2) to determine the scope and generality of the suggested protocol.

The obtained products 3b and 3c were in complete agreement with the spectroscopic data. For example, the IR spectrum of compound 3b showed a C=N band at 1609 cm⁻¹ and two asymmetric bands at 3193 and 3271 cm⁻¹ due to the amino group. The ¹HNMR spectrum of the same compound exhibited two dd signals at δ 3.99 and 4.18 ppm due to Ha and Hb, respectively, and another dd signal at δ 5.58 ppm due to the Hx proton, and one singlet signal (D₂O-exchangeable) assigned to NH₂ protons at δ 6.36 in addition to aromatic protons and furan protons as a multiplet at δ 7.15–7.92 ppm. The applied protocol displayed excellent results (high yields and short reaction time) for both obtained compounds (cf. experimental part). Also, we extended our scope to include other nitrogen nucleophiles, such as 3-amino-1,2,4-triazole (6) and 2-amino benzimidazoles (7) under the same optimized reaction conditions (Scheme 3).

However, in each case, only one isolable product was obtained with an excellent percentage yield and short reaction time (cf. experimental part). The formed product 7 was found in its oxidized form rather than its dihydro form, as proved by ¹H NMR. For example, the ¹H NMR spectrum of compound 7 revealed two singlet signals at δ 7.51 and 8.48 due to the pyrimidine proton CH-6 and triazole-CH-2, respectively, in addition to aromatic protons and furan protons as a multiplet at δ 7.19–8.25. This attitude for such an oxidation process proceeded predominantly for the case of using 3-amino-1,2,4-triazole with chalcone in a basic medium [34]. The structure of compound 9 was in line with obtained spectroscopic data in which the ¹H NMR spectrum exhibited two dd signals at δ 3.29 and 3.52 ppm due to Ha, Hb, respectively, alongside another dd signal at δ 5.60 ppm due to the Hx proton, two doublet signals at δ 5.19 and 6.69 due to the furan protons H-3, H-5, respectively, and aromatic protons and the furan proton H-4 as a multiplet at δ 6.72–7.77 ppm. According to the previous report [16], Mg Al-HT contains Lewis acidic sites due to Al³⁺ and the Brønsted basic sites due to (OH⁻), which exert their catalytic action first via the adsorption of the amine lone pair to acidic sites, accompanied by a deprotonation/re-protonation process that assists the nucleophilic addition to endo nitrogen and affords the Michael adduct which is subjected to cyclization via dehydration and produces azolo[1,5-a]pyrimidine derivatives (Scheme 4).

Figure 4 clarifies the reusability of Mg Al-HT for the synthesis of compound 3a tested under a Q-tube system in which it was found that the reaction was repeated seven times using a regenerated catalyst. Each time the catalyst was removed after the reaction finished (as examined by TLC) via filtration, it was washed with hot ethanol and sonicated in ethyl acetate for 10 min to desorb all adsorped organic materials before drying under a vacuum. The recovered catalyst was reused seven times and the time required to accomplish the reaction, and the % yield were taken as an indication of catalytic activity. It is noteworthy that this reusability study not only addressed the catalytic activity of the used heterogeneous catalyst but also provided insights inon the reproducibility of the Q-tube system.

Finally, we succeeded in confirming and ascertaining the economic and reproducible high-pressure green system “Q-tube” for organic synthesis.

3. Materials and Methods

All experimental details are depicted in the Supplementary File which includes the preparations of the starting materials [35,36] according to the reported literature also, the green metric such atom economy equation [37] for the reaction.

4. Conclusions

The green reaction method demonstrated herein provides an economical and sustainable alternative to other standard organic synthesis methods, including microwave irradiation; our protocol was attained using a high-pressure Q-Tube reactor toward achieving the aza-Michael addition reaction to synthesize fused azine derivatives utilizing the heterogeneous as-synthesized Mg-Al-HT catalyst. This catalyst showed superior catalytic activity and ability for reuse until the seventh ran without losing its catalytic activity. When compared to conventional heating methods, Q-tubes with a Qian cap had the fastest reaction time and high percentage yield. By using the Q-tube technique, we are able to work on new substrates for biological screening in the future in an economical way rather than using microwave reactors.