Q-Tube Assisted Green Synthesis of Bis(Azoles) and Bis(Azines) Linked to Arene Unit

Abstract We reported herein efficient green procedures for the synthesis of arene-linked bis(azoles) and bis(azines) using bis(enaminone) as a key intermediate. For this purpose, bis(enaminone) were reacted with different nucleophiles under a pressurized reaction “Q-tube system” to afford the target bis(azoles) and bis(azines). The structures of the target compounds were confirmed via considering their elemental analyses as well as their spectral data. The used protocol shows a beneficial effect on the reaction time and yields compared to conventional conditions.


Introduction
Organic chemistry plays an essential role in the pharmaceutical industry that continues to be one of the main drivers in the drug discovery process. Organic chemists always work to release different technologies for the synthetic methods of novel compounds. 1 High-pressure organic synthesis is considered one of the technologies that obtain faster and cleaner transformation by simply modifying some physical properties of solvents, reagents, and final products. [2][3][4][5][6][7][8] Overcoming the solvent's boiling point is the main advantage of a reaction under pressure. 8 Among the devices developed for high-pressure chemistry, Q-tubeV R provided by Q Labtech is undoubtedly the most straightforward and cheapest alternative. 9 a Q-tube is a patented, safe pressure reactor featuring a pressure release and reseals system that prevents explosions due to overpressures. It is considered a viable alternative to expensive MW synthesizers, but at the same time, it is also suitable for those solvents that are MW transparent.
Noteworthy, the main effect of Q-Tube that enhances the organic reaction lies behind two factors: the first is making a reaction at a higher temperature over the boiling point of the solvent, which increases the reaction rate. According to the Arrhenius concept (Arrhenius equation: every 10 C increase could double the speed)-Equation (1). The second is that high pressure reduces reaction volume, including liquid which increases concentration and collision frequency and speeds up a reaction. Pressure enables faster reactions with cleaner profiles. When the desired reaction is accelerated, the competing reagent decompositions are minimized.

Results and discussions
The synthetic procedures adopted to obtain the target compounds are depicted in Schemes 1-3. The reaction of 1,4-diacetylbenzene (1) with dimethylformamide-dimethylacetal (DMF-DMA) (2) was carried out in slight excess of DMF-DMA under reflux and Q-tube reactor and yielded a single product in each case [as examined by thin-layer chromatography (TLC)] that was identified as (2E,2 0 E)-1,1 0 -(1,4-phenylene)bis(3-(dimethylamino)prop-2-en-1-one) (3) (Scheme 1). It was found that by using a high-pressure reactor (Q-tube), a high percentage of yield with short time preparation versus the reported traditional method was observed. 40,41 An approximate percent of yield with the previously reported microwave radiation method. 42 The comparative results between the two preparation methods are shown in Scheme 1.
The elemental analysis and spectral data agree entirely with structure 3 for the two preparation methods. For example, its 1  in the E-configuration. The bis(enaminone) 3 encouraged us to study their synthetic utilities as building blocks for novel bis(pyrazoles) and bis(isoxazoles) via condensation reaction with hydrazine hydrate and hydroxylamine, respectively. Compound 3 reacts with hydrazine monohydrate in ethanol utilizing the high-pressure reactor Q-Tube. It afforded only one product identified as bis pyrazole derivative 4 (Scheme 2). Its 1 HNMR spectroscopy of 4 recorded doublets for CH-4 pyrazole at 6.74 ppm while CH-5 pyrazole at 7.55 ppm. When compound 3 is allowed to condense with the hydroxylamine hydrochloride in the presence of sodium carbonate in ethanol utilizing the high-pressure reactor Q-Tube. Also, one product only observed in TLC was identified as bis(isoxazole) 5. It is evident by 1 HNMR d 8.69 (d, J ¼ 1.82 Hz CH-5 isoxazole) at downfield while d 7.15 (d, J ¼ 1.82 Hz CH-4 isoxazole) at upfield, which is in complete agreement with the proposed structure depicted in Scheme 2. Noteworthy, to find a beneficial effect of the high-pressure reactor on the reactions shown in Scheme 2, these reactions had been done under conventional heating. In the case of compound 4, almost the exact reaction yield but short reaction time were noticed with the High-pressure Q-Tube reactor. Time of reactions and % yield is represented in Scheme 2.
Bis(enaminone) 3 was a precursor for synthesizing bis(azines) 6-8 via reaction with guanidine, thiourea, and malononitrile utilizing the Q-tube reactor; in each case, only one product formed. (Scheme 3). The reactions of dienaminone 3 with guanidine hydrochloride, urea, and/or thiourea give the corresponding pyrimidine in excellent yields and the shortest reaction time utilizing the high-pressure Q-tube in comparison with conventional heating (Scheme 3). In the case of compound 6, the IR spectrum shows two symmetric and asymmetric bands at 3467; 3283 cm À1 due to NH 2 group, and its 1 H NMR shows D 2 O exchangeable singlet signal due to 4 hydrogens at 6.72, which represent the amino group.
IR spectrum of compound 7 exhibits a distinguished absorbance band due to C ¼ S at 1434 cm À1 and the signal in 13  compound formed as examined by TLC in a satisfied % yield. The formed compound was identified as bis(pyridine) via arene bridge compound 8. The IR spectrum of the formed compound 8 shows a band at 2174 cm À1 due to the cyano group. 1 HNMR in complete agreement with the formed compound (cf. Experimental part). It was clear from Scheme 3 that the formed compounds utilizing the high-pressure Q-tube have a high % yield with a short-time reaction versus the conventional heating method. It is worth mentioning that all reactions above are proceeded via aza-Michael addition reaction mechanism of nitrogen nucleophiles into a,b-unsaturated ketone followed by cyclization.

Conclusions
The study described here led to the development of an efficient green protocol that saves energy via utilizing the high-pressure Q-tube reactor for organic synthesis. The protocol has used the bis(enaminone) linked to the arene unit as the precursor for bis azoles and bis azines. In general, the modern method Q-tube proves the shortest reaction time versus the conventional heating method.

General
All melting points were measured on a Gallenkamp Electrothermal melting points apparatus and were uncorrected. The Infrared spectra (KBr disks) in 4000-400 cm À1 were recorded on Perkin-Elmer Frontier spectrometer (USA). The second IR device is Spectrum Two FT-IR Spectrometer, detector type LiTaO 3 , wavelength range 8300-350 cm À1 . The NMR spectra were recorded on 850 and 600 MHz NMR spectrometer deuterated in dimethylsulfoxide (DMSO-d 6 ) and chloroform deuterated (CDCl 3 ). Chemical shifts are quoted in d and were related to that of the solvent. The mass spectrum was carried out on a direct probe controller inlet part to a single quadrupole mass analyzer in (Thermo Scientific GCMS) (Model (ISQ LT) using Thermo X-Calibur Software at the regional center for mycology and biotechnology (RCMB) Al-Azhar University, NASER city, Cairo. The reaction temperature was manual input depending on the boiling point of the solvent used and stabilized even more than an hour. Q-tube-assisted reactions were performed in a Qtube safe pressure reactor from Q Labtech, equipped with a cap/sleeve, pressure adapter (120 psi), needle, borosilicate glass tube, Teflon septum, and catch bottle. Elemental analyses were performed using Perkin-Elmer 2400 Analyzer. TLC Sigma-Aldrich, Silica gel on TLC Al foils, silica gel matrix, with fluorescent indicator 254 nm.

General procedure for preparation of dienaminone 3
Method I: A mixture of compound 1 (10 mmol) and DMFDMA (25 mmol) were refluxing at 90-100 C overnight. The mixture left to room temperature, solid was collected by hexane, and petroleum ether 40-60 then wash by ethanol Method II: The same above mixture scale was placed in a Q-tube at 120 C/under the autogenic pressure (

General procedure for preparation of bis(azoles) 4 and 5
Method I. For bis(pyrazoles): A mixture of compound 3 (10 mmol) and hydrazine monohydrate (20 mmol) in ethanol was refluxing at 50-60 C for 120 min. A mixture was left to cool, then added on iced water. Solid filtered and washed by EtOH then collected the product. For bis(isoxazoles): A mixture of compound 3 (10 mmol), hydroxylamine hydrochloride (25 mmol), and sodium carbonate (25 mmol) in EtOH were refluxing at 50-60 C for 240 min. A mixture was left to cool, then added on iced water. The solid was collected by filtration and washed with EtOH.
Method II. The same above mixture scales were placed in a Q-tube at 120 C/under the autogenic pressure of 30 psi for an appropriate time as examined by TLC. Then the products were obtained by following the same workup mentioned above. Method I: A mixture of compound 3 (10 mmol), guanidine hydrochloride, urea, or thiourea (20 mmol) then added sodium ethoxide (30 mmol) in EtOH were refluxing at 60-70 C for the appropriate time as examined by TLC. A mixture left to cool. The solid was collected by filtration washed with EtOH.
Method II: The same above mixture scales were placed in a Q-tube at 120 C/under the autogenic pressure of 30psi for an appropriate time as examined by TLC. the products were collected and washed by ethanol crystallization by DMF. Method I: A mixture of compound 3 (10 mmol), malononitrile (20 mmol), and piperidine drops in EtOH were refluxed at 75 C for 420 min. Solid filtered and washed by EtOH then collected the product.
Method II: The same above mixture scale was placed in a Q-tube at 120 C/under the autogenic pressure of 30 psi for an appropriate time as examined by TLC. The product was collected and washed by ethanol crystallization EtOH.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Funding
The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia, for funding this research work through the project number MoE-IF-G-20-04.