Reactions under increased pressure: The reactivity of functionally substituted 3-oxo-2-arylhydrazones toward active methylene reagents in Q-tube European Journal of Chemistry 12 (2) (2021) 154-158 European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2021 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. https://dx.doi.org/10.5155/eurjchem.12.2.154-158.2065 European Journal of Chemistry View Journal Online View Article Online Reactions under increased pressure: The reactivity of functionally substituted 3-oxo-2-arylhydrazones toward active methylene reagents in Q-tube Douaa Salman AlMarzouq * Department of Environmental Health, College of Health Sciences, The Public Authority of Applied Education and Training, Faiha, 72853, Kuwait ds.almarzouq@paaet.edu.kw (D.S.A.) * Corresponding author at: Department of Environmental Health, College of Health Sciences, The Public Authority of Applied Education and Training, Faiha, 72853, Kuwait. e-mail: ds.almarzouq@paaet.edu.kw (D. S. AlMarzouq). 10.5155/eurjchem.12.2.154-158.2065 Received: 10 January 2021 Received in revised form: 27 January 2021 Accepted: 21 April 2021 Published online: 30 June 2021 Printed: 30 June 2021 A one-pot two-component reaction of 3-oxo-2-arylhydrazones with active methylene nitriles under high pressure in a Q-tube safe reactor was reported. Comparison between conventional and Q-tube safe reactor-assisted synthesis of organic compounds was done by comparing total reaction time and percentage yield. The results show that the compound 5-cyano-6-oxo-1,4-diphenyl-1,6-dihydro- pyridazine-3-carboxylic acid ethyl ester (3) was synthesized within 2 h in a yield of 97%. In addition, the pyrazolo[3,4-c]pyridines 5b and 5c were obtained in yields of 93 and 95% within 1 h reaction time, respectively. The obtained results suggest that Q-tube safe reactor-assisted syntheses were led to higher product yields within very short reaction times. Q-tube Record time Green technology 3-Oxo-2-arylhydrazones Multi-component reaction Reaction under increased pressure Cite this: Eur. J. Chem. 2021, 12(2), 154-158 Journal website: www.eurjchem.com 1. Introduction Recently, our group was involved in consequently a program aimed at utilizing 3-oxo-2-arylhydrazones as precursors to heteroaromatics [1]. Several of which were patented for diverse utilities [2,3]. Our contribution in this area has been recently surveyed [4,5], and major results are outlined in Scheme 1 and 2. Since 1997 [6], we have investigated extensively the utility of microwave to accelerate reaction rates. However, we recently realized that the microwave is just heating at a temperature higher than that of the media as the polar reactants are form hot spots and then release temperature to the reaction media [7]. The microwave technology is expensive to scale up [8] and no industrial example utilizing it exists accordingly there is a need for employing neoteric energy sources to increase energy efficiency. The pressure also allows reactions to proceed at temperatures higher than those of the media. It also increases the rate of reaction conditions and enhances the formation of transition state with negative activation volume [9]. As a result of this, we turned to utilize reactions in Q-tube (a safety device that enables conducting reactions in the laboratory), and successfully we could produce several articles whose results are outlined in Scheme 3 and 4 [10-12]. Our aim is to develop a novel and efficient protocol for the synthesis of cyclic derivatives with multi-component reaction (MCR) which includes a condensation reaction utilizing a Q-tube safe reactor in a short time with high yield. 2. Experimental 2.1. Instrumentation Infrared spectra were recorded using dry KBr pellets and a Jasco vacuum FT-IR 6300 instrument and absorption bands are reported in cm-1. 1H- and 13C-NMR spectra were determined by using a Bruker DPX instrument at 400 or 600 MHz for 1H-NMR and 100 or 125 MHz for 13C-NMR and either CDCl3 or DMSO-d6 solutions with TMS as internal standards. Chemical shifts are reported in ppm. Mass spectra and accurate mass measure- ments were made using a GC-MS DFS Thermo spectrometer with the EI (70 eV) mode. All reactions were monitored by using TLC with ethyl acetate: petroleum ether (1:1, v:v) as eluent and were carried out until starting materials were completely consumed. ABSTRACT RESEARCH ARTICLE KEYWORDS https://dx.doi.org/10.5155/eurjchem.12.2.154-158.2065 https://www.eurjchem.com/ https://dx.doi.org/10.5155/eurjchem.12.2.154-158.2065 mailto:ds.almarzouq@paaet.edu.kw mailto:ds.almarzouq@paaet.edu.kw http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.12.2.154-158.2065&domain=pdf&date_stamp=2021-06-30 Douaa Salman AlMarzouq / European Journal of Chemistry 12 (2) (2021) 154-158 155 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.2.154-158.2065 Scheme 1 Scheme 2 Scheme 3 156 Douaa Salman AlMarzouq / European Journal of Chemistry 12 (2) (2021) 154-158 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.2.154-158.2065 Scheme 4 Scheme 5 Sonication was performed in MKC6 Guyson ultrasonic bath (Model-MKC6, operating frequency 38 kHz +/- 10% and output power of 110 Watts) with a digital timer (6 sec. to 100 min.) and the heater allows solution heating to be set from 20 to 80 °C in 1 °C increment. The inside tank dimensions are 150 × 300 × 150 mm (length × width × depth) with a fluid capacity of 6 liters. Q- tube-assisted reactions were performed in a Q-tubeTM safe pressure reactor from Q Labtech, equipped with a cap/sleeve, pressure adapter (120 psi), needle adapter/needle, borosilicate glass tube, Teflon septum, and catch bottle. 2.2. Synthesis 2.2.1. Synthesis of compounds 1a-c 3-Oxo-3-phenyl-2-(phenyl-hydrazono)-propionic acid ethyl ester (1a), 3-oxo-3-phenyl-2-(2-(p-tolyl)hydrazono)propanal (1b) and 3-oxo-3-(4-chlorophenyl)-2-(2-phenylhydrazono) propanal (1c) were prepared according to previously published methods [11,13]. 2.2.2. Synthesis of 5-cyano-6-oxo-1,4-diphenyl-1,6-dihydro- pyridazine-3-carboxylic acid ethyl ester (3) Mixture of the 3-oxo-3-phenyl-2-(phenyl-hydrazono)- propionic acid ethyl ester (1a) (1.0 g, 3.0 mmol) and malono- nitrile (2) (0.3 g, 4.5 mmol) in acetic acid (10 mL), and ammonium acetate (1.0 g) sequentially added in a 35 mL Q- tube, furnished by Q Labtech. A Teflon septum was placed on the top of the tube, and an appropriate cap and pressure adapter were used. The mixture was heated in an oil bath at 130 °C. After about 2 h, the reaction mixture was monitored by TLC and GC/MS and stopped. The hot reaction mixture was filtrated and washed with ethanol. The separated solid products obtained on standing at room temperature were collected by filtration, washed with ethanol (Scheme 5). 5-Cyano-6-oxo-1, 4-diphenyl-1, 6-dihydro-pyridazine-3- carboxylic acid ethyl ester (3): Color: Yellow. Yield: 97%. M.p.: 80-82 °C. FT-IR (KBr, ν, cm-1): 1731, 1666 (CO), 2223 (CN). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.26 (t, 3H, J = 6.6 Hz, OCH2CH3), 4.32 (q, 2H, J = 6.6 Hz, OCH2CH3), 7.05 (t, 1H, J = 7.2 Hz, Ar-H), 7.26-7.29 (m, 2H, Ar-H), 7.32 (t, 2H, J = 7.8 Hz, Ar-H), 7.54 (t, 2H, J = 7.2 Hz, Ar-H), 7.64-7.65 (m, 1H, Ar-H), 7.85-7.86 (m, 2H, Ar-H). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 13.89, 61.06, 114.49, 123.76, 125.74, 129.06, 132.35, 137.34, 137.72, 140.22, 142.42, 149.96, 156.18, 161.59, 172.26, 188.88, 192.26, 206.49. Douaa Salman AlMarzouq / European Journal of Chemistry 12 (2) (2021) 154-158 157 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.2.154-158.2065 Table 1. The % yield products and reaction time. Method Product (3) Product (5b) Product (5c) Time (h) Yield (%) Time (h) Yield (%) Time (h) Yield (%) Conventional No product No product 8 93 8 94 Q-tube 2 97 1 93 1 95 Scheme 6 MS (EI, m/z (%)): 346.1 (M+, 19), 345.1 (M, 100), 77 (90). HRMS (EI, m/z) calcd. for C20H15O3N3, 345.1108; Found: 345.1107. 2.2.3. General procedure for the preparation of compounds 4b,c Independent mixtures of 3-oxo-3-phenyl-2-(2-(p-tolyl) hydrazono)propanal (1b) and 3-oxo-3-(4-chlorophenyl)-2-(2- phenylhydrazono)propanal (1c) derivatives (5 mmol), ben- zoylacetonitrile (0.725 g, 5 mmol), and ammonium acetate (1 g) in acetic acid (10 mL) sequentially added in a 35 mL Q-tube pressure tube. The progress of the reactions was monitored by using TLC and 1:1 ethyl acetate/petroleum ether as eluent. A Teflon septum was placed on the top of the tube, and an appropriate cap and pressure adapter were used. The mixture was heated in an oil bath at 140 °C. After about 30 min, the mixtures were cooled to room temperature. The formed solids were collected by filtration and crystallized from the indicated solvents to give 2, 6-diphenyl-5-(p-tolyldiazenyl)nicotinonitrile (4b) (84%, [14]) and 6-(4-chlorophenyl)-2-phenyl-5-(phenyl diazenyl)nicotinonitrile (4c) (90%, [14]) as pure products (Scheme 6). 2.2.4. Synthesis of pyrazolo[3,4-c]pyridines (5b,c) Independent mixtures of compounds 4b or 4c (2.5 mmol) in dry toluene (10 mL), containing N,N-dimethylformamide- dimethylacetal (DMF-DMA) (0.5 mL, 5 mmol) sequentially added in a 35 mL Q-tube pressure tube. A Teflon septum was placed on the top of the tube, and an appropriate cap and pressure adapter were used. The mixture was heated in an oil bath at 140 °C. After about 1 h, the reaction mixture was monitored by TLC and GC/MS and stopped. The hot reaction mixture was filtrated and washed with ethanol while the %yield was calculated and compared with the reported method. The separated solid products (5b (93%, [14]) and 5c (%94, [14])) obtained on standing at room temperature were collected by filtration, washed with ethanol (Scheme 6). 3-(Dimethylamino)-5, 7-diphenyl-2-p-tolyl-2H-pyrazolo[3, 4- c]pyridine-4-carbonitrile (5b): Color: Orange. Yield: 93%. M.p.: 220-221 °C. FT-IR (KBr, ν, cm-1): 2215 (CN). 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.46 (s, 3H, Ar-CH3), 2.88 (s, 6H, 2CH3), 7.47 (d, J = 8.4 Hz, 2H, Ar-H), 7.57-7.63 (m, 8H, Ar-H), 8.02 (d, 2H, J = 8.0 Hz, Ar-H), 8.73-8.76 (m, 2H, Ar-H). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 20.81, 43.40, 94.04, 118.56, 120.23, 125.57, 128.18, 128.43, 128.57, 129.29, 129.75, 131.11, 135.89, 136.70, 138.11, 138.29, 139.51, 140.14, 143.88, 151.98, 152.25. MS (EI, m/z (%)): 430 (M+, 25.88), 429 (M, 100). HRMS (EI, m/z) calcd. for C28H23N5, 429.1948; Found: 429.1948. 7-(4-Chlorophenyl)-3-(dimethylamino)-2, 5-diphenyl-2H- pyrazolo[3,4-c]pyridine-4-carbonitrile (5c): Color: Orange. Yield: 95%. M.p.: 230-231 °C. FT-IR (KBr, ν, cm-1): 2212 (CN). 1H NMR (600 MHz, DMSO-d6, δ, ppm): 2.88 (s, 6H, 2CH3), 7.56-7.70 (m, 8H, Ar-H), 7.75 (d, J = 8.4 Hz, 2H, Ar-H), 8.01 (d, J = 7.2 Hz, 2H, Ar-H), 8.79 (d, J = 8.4 Hz, 2H, Ar-H). 13C NMR (150 MHz, DMSO-d6, δ, ppm): 43.35, 94.46, 118.39, 120.29, 124.59, 125.83, 128.44, 128.83, 129.37, 129.41, 129.68, 129.80, 131.38, 134.57, 136.09, 137.93, 139.04, 140.10, 144.14, 150.53, 152.17. MS (EI, m/z (%)): 450 (M+, 47), 449 (M, 100), 77 (13). HRMS (EI, m/z) calcd. for C27H20ClN5, 449.1402; Found: 449.1402. 3. Results and discussion In continuation to our interest in exhibiting the merits of performing reactions under increased pressure utilizing a Q- tube safe reactor, we investigated the reaction of compounds 1a-c with active methylene in a multi-component reaction. We 158 Douaa Salman AlMarzouq / European Journal of Chemistry 12 (2) (2021) 154-158 2021 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.12.2.154-158.2065 were unable to obtain compound 3 via condensation reaction of compound 1a with malononitrile via the conventional heating method in multi-component reaction (MCR) (Table 1). In this study, we found that the condensation of compound 1a with malononitrile 2 in Q-tube produces compound 3 in excellent yield, where the only isolable product was compound 3 (Scheme 5). We were compared with the nature of the reaction product and its rate and yield with the reported products, yield, and rates. It could be concluded that the readily scalable reactions under these conditions can proceed at rates comparable to those conducted in the microwave and in some multi-component reaction reactions under increased pressure produce different products perhaps by changing the sequences of these reactions. In addition, the compounds 1b and 1c were reacted with benzoyl acetonitrile to yield compounds 4b and 4c. The obtained compounds 4b and 4c were reacted with dimethylformamide-dimethyl acetal (DMF-DMA) to yielding compounds 5b and 5c (Scheme 6). We found that compounds 4b, 4c, 5b, and 5c are produced under increased pressure at much faster rates and higher yields in this study via Q-tube (Table 1, Scheme 6). 4. Conclusion A new route of green chemistry using a new technique in which the reactions occur under increased pressure in Q-tube revealed that the important of the reaction yields with a record time was achieved. In conclusion, the method of Q-tube represents a promising benign route to replace many conven- tional basic methods. The utility of the Q-tube method showed the acceleration of several reactions in a better way. It is a logical outcome after several researches and comparisons with several old methods, that an improvement of the reaction yields with a record time was achieved. Acknowledgments The author is deepest grateful to Prof. Mohamed Hilmy Elnagdi for his continual guidance during performing this work and to Prof. Kamal Usef Sadek for his consultations. We are also grateful to Dr. Hamada Ibrahim for his support and discussion of the results. Thankful to Kuwait University Research Administration-RSP unit general facilities of the Faculty of Science, GFS GS 02/01, GS 03/01, GS 01/05). Disclosure statement Conflict of interests: The author declares that he has no conflict of interest. Ethical approval: All ethical guidelines have been adhered. Sample availability: Samples of the compounds are available from the author. ORCID Douaa Salman AlMarzouq https://orcid.org/0000-0002-4633-8168 References [1]. Abdelhamid, I.; Elnagdi, M.; Nasra, M. Synlett. 2009, (20), 3237–3251. [2]. Konkoy, C. 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S.; Elnagdi, M. H. Tetrahedron Lett. 2016, 57 (32), 3596–3599. [11]. Moustafa, M. S.; Al-Mousawi, S. M.; Elnagdi, M. H. RSC Adv. 2016, 6 (93), 90840–90845. [12]. AlMarzouq, D. S.; Zaky, O. S.; AlNajjar, A. A.; Sadek, K. U. Eur. J. Chem. 2016, 7 (3), 347–351. [13]. Makhseed, S.; Hassaneen, H. M. E.; Elnagdi, M. H. Z. Naturforsch. B J. Chem. Sci. 2007, 62 (4), 529–536. [14]. Behbehani, H.; Ibrahim, H. M. A. Tetrahedron 2013, 69 (49), 10535– 10543. Copyright © 2021 by Authors. This work is published and licensed by Atlanta Publishing House LLC, Atlanta, GA, USA. The full terms of this license are available at http://www.eurjchem.com/index.php/eurjchem/pages/view/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (http://www.eurjchem.com/index.php/eurjchem/pages/view/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). https://orcid.org/0000-0002-4633-8168 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms http://creativecommons.org/licenses/by-nc/4.0 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms 1. Introduction 2. Experimental 2.1. Instrumentation 2.2. Synthesis 2.2.1. Synthesis of compounds 1a-c 2.2.2. Synthesis of 5-cyano-6-oxo-1,4-diphenyl-1,6-dihydro-pyridazine-3-carboxylic acid ethyl ester (3) 2.2.3. General procedure for the preparation of compounds 4b,c 2.2.4. Synthesis of pyrazolo[3,4-c]pyridines (5b,c) 3. Results and discussion 4. Conclusion Disclosure statement ORCID References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: