untitled European Journal of Chemistry 7 (3) (2016) 347‐351 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2016 Atlanta Publishing House LLC ‐ All rights reserved ‐ Printed in the USA http://dx.doi.org/10.5155/eurjchem.7.3.347-351.1473 European Journal of Chemistry Journal webpage: www.eurjchem.com Pressure as effective green technology for synthesis of polyfunctionally substituted heteroaromatics : Synthesis of a variety of pyrazolo[1,5‐a]pyrimidines Douaa Salman AlMarzouq 1,*, Omniya Sayed Zaky 1, Abdulaziz Abdulrazaq AlNajjar 2 and Kamal Usef Sadek 3 1 Department of Chemistry, Faculty of Science, South Valley University, Qena, 83511, Egypt 2 Department of Applied Science, Faculty of Technological Studies, Public Authority for Applied Education and Training, 42325 Safat, 70654, Kuwait 3 Department of Chemistry, Faculty of Science, Minia University, Minia, 61519, Egypt * Corresponding author at: Department of Chemistry, Faculty of Science, South Valley University, Qena, 83511, Egypt. Tel.: +965.97932529. Fax: +965.97932529. E‐mail address: nontan_83@hotmail.com (D. AlMarzouq). ARTICLE INFORMATION ABSTRACT DOI: 10.5155/eurjchem.7.3.347-351.1473 Received: 30 June 2016 Received in revised form: 20 July 2016 Accepted: 23 July 2016 Published online: 30 September 2016 Printed: 30 September 2016   Pyrazole molecules are in the forefront of organic chemistry due to their various encompass substituents, which have many biological activity sequence. The biological and medicinal activities of pyrazolo[1,5‐a]pyrimidines have received considerable interest in this regard. We reported here a comparison between reaction of 4‐phenylazo‐3,5‐diaminopyrazole (4) with ethyl propiolate (15), dimethylacetylene dicarboxylate (20), diethyl fumarate (25) and benzylidenemalononitrile (11) in the presence of catalytic amount of piperidine. We initially followed literature procedure (method A), then utilizing ultrasound irradiation (method B), microwave heating (method C) and in a Q‐tube (method D). We confirmed the structure of the product by analytical spectroscopic methods. Method (D) gave a good yield with a record reaction time. KEYWORDS Q‐tube High yields Record time Green technology Pyrazolo[1,5‐a]pyrimidines Reactions under increased pressure Cite this: Eur. J. Chem. 2016, 7(3), 347‐351 1. Introduction 4‐Arylazopyrazole‐3,5‐diamines (4), first synthesized by Elnagdi and Abdulla [1] have found plenty of applications initially as hair dyes [2], antibacterial agent [3] and recently as efficient cyclin‐dependent kinases (CDK) inhibitors [4]. Elnagdi et. al. [5‐8] have reported that while 4‐arylazo‐ pyrazole‐3,5‐diamines react with acrylonitrile and ethyl acrylate (5a,b) to yield 4‐(3,5‐diamino)‐4‐(phenyldiazenyl)‐ 1H‐pyrazol‐1‐yl)butanenitrile or ethyl(3,5‐diamino‐4‐(phenyl diazenyl)‐1H‐pyrazol‐1‐yl)butanoate (6a,b) that could be cyclized into 2‐amino‐3‐(phenyldiazenyl)pyrazolo[1,5‐a]pyri‐ midin‐5(4H)‐one (7) upon reflux in AcOH (Scheme 1). Similarly, 4‐arylazopyrazole‐3,5‐diamines reacted with phenyl isothiocyanate (8) to afford 3,5‐diamino‐N‐phenyl‐4‐(phenyl diazenyl)‐1H‐pyrazole‐1‐carbothioamide (9). Attempted cyclisation of compound 9 via refluxing in AcOH afforded the N,N’(4‐phenyldiazenyl)‐1H‐pyrazole‐3,5‐diyl)diacetamide (10). On other hand, reaction of 4‐arylazopyrazole‐3,5‐ diamines with arylidene malononitrile (11) and enaminones (13) in refluxing pyridine has been reported to afford 2,7‐ diamino‐5‐phenyl‐3‐(phenyldiazenyl)pyrazolo[1,5‐a]pyrimi‐ dine‐6‐carbonitrile (12) and 7‐aryl‐3‐(phenyldiazenyl)pyra‐ zolo[1,5‐a]pyrimidine (14) via initial attack at exocyclic amino function and cyclization (Scheme 1). Because of potential utility of the chemistry in Scheme 1 in fine chemical industry it looked of value to optimize reaction conditions and confirmed concluded structures as only few pyrazolo[1,5‐a]pyrimidine derivatives have been reported in the literature [9‐17]. Although several pyrazolopyrimidine‐7‐ ones have been synthesized and tested for a variety of activities, only few isomeric‐5‐ones have ever been synthe‐ sized. In this article, we will examine if terminal alkynes will react initially with 4‐arylazopyrazole‐3,5‐diamines (4) to yield ring N‐alkylated derivatives that can be cyclized into the corresponding 5‐ones thus developing a route for preparing such derivatives as only Elnagdi has claimed ring alkylation in cyanoethylation [14]. 348 AlMarzouq et al. / European Journal of Chemistry 7 (3) (2016) 347‐351 Scheme 1 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 MHz or 600 MHz for 1H NMR and 100 MHz or 150 MHz for 13C NMR and either deuterated chloroform (CDCl3) or deuterated dimethyl sulphoxide (DMSO‐d6) solutions with tetramethylsilane (TMS) as internal standards. Chemical shifts are reported in part per million (ppm). Mass spectra and accurate mass measurements were made using a GC‐MS DFS Thermo spectrometer with the EI (70 eV) mode. All reactions were monitored by using thin layer chromatography (TLC) with 1:1 ethyl acetate:petroleum ether as eluent and were carried out until starting materials were completely consumed. Sonication was performed in MKC6, Guyson ultrasonic bath (Model‐MKC6, operating frequency 38 kHz +/‐ 10% and an output power of 110 Watts) with digital timer (6 sec. to 100 min.) and heater allows solution heating to be set from 20 to 80 °C in 1 °C increments. 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 2‐(phenyl‐hydrazono)‐malononitrile (3) Phenylamine (Aniline) (1) (9.3 g, 0.10 mol) added to 100 g ice and 100 mL water in 500 mL beaker and then slowly added around 10 mL of 33% hydrochloric acid with stirring. Prepared a solution of sodium nitrite (6.9 g, 0.10 mol) by dissolved in less amount of water. Slowly added the sodium nitrite solution to the phenylammonium chloride solution with continual cooling so that the temperature of the reaction never goes above 10 °C. Leaving it, in the ice bath at all times to keep the reaction mixture as cold as possible. Prepared a solution of malononitrile (6.6 g, 0.10 mol) in roughly amount of ethanol with 4.0 g of sodium hydroxide and poured it into a stirred solution of benzenediazonium chloride (2). The resulting precipitate was collected by filtration and washed with water, then air‐dried. Purification was achieved by using extraction in ethanol and gave the pure desired product (Scheme 1). Color: Yellow powder. Yield: 95%. M.p.: 153‐156 °C. FT‐IR (KBr, , cm‐1): 3195 (NH), 2231, 2210 (CN), 1603 (C=N). 1H NMR (600 MHz, DMSO‐d6, δ, ppm): 7.19 (t, 1H, J = 7.2 Hz, Ar‐H), 7.40 (t, 2H, J = 8.4 Hz, Ar‐H), 7.45 (d, 2H, J = 8.4 Hz, Ar‐H) 13.05 (br. s, 1H, NH). 13C NMR (150 MHz, DMSO‐d6, δ, ppm): 83.95, 111.09, 115.62, 117.20, 126.17, 129.93, 143.02 (Ar‐C and CN). MS (EI, m/z (%)): 171 (M+1, 5), 170 (M+, 60), 77 (100). HRMS (EI, m/z) calcd. for C9H6N4, 170.0587; found 170.0587. 2.2.2. Synthesis of 4‐phenylazo‐1H‐pyrazole‐3,5‐diamine (4) To a stirred 2‐(phenyl‐hydrazono)‐malononitrile (3) (3.0 g, 17.50 mmol) in absolute ethanol (50 mL) was added hydrazine hydrated (1.0 g, 20 mmol) at room temperature for 1 h. The reaction mixture was monitored by TLC. The solid product was collected by filtration and washed with ethanol. Color: Free‐flowing bright yellow powder (Scheme 1). Yield: 98%. M.p.: 260‐264 C. FT‐IR (KBr, , cm‐1): 3291, 3183 (NH2), 3392 (NH). 1H NMR (600 MHz, DMSO‐d6, δ, ppm): 6.10 (br. s, 4H, NH2), 7.20 (t, 1H, J = 7.2 Hz, Ar‐H), 7.38 (t, 2H, J = 8.4 Hz, Ar‐H), 7.62 (d, 2H, J = 8.4 Hz, Ar‐H), 10.73 (br. s, 1H, NH). AlMarzouq et al. / European Journal of Chemistry 7 (3) (2016) 347‐351 349 Scheme 2 13C NMR (150 MHz, DMSO‐d6, δ, ppm): 114.16, 120.41, 126.51, 128.71, 153.50. MS (EI, m/z (%)): 203 (M+1, 11), 202 (M+, 100), 125 (M, 68). HRMS (EI, m/z) calcd. for C9H10N6, 202.0961; found 202.0961. 2.3. General procedure synthesis of pyrazolo[1,5‐a] pyrimidine derivatives 2.3.1. Method A (Thermal heating) Independent mixture of 4‐phenylazo‐1H‐pyrazole‐3,5‐ diamine (4) (0.5 g, 2.5 mmol) and 2.5 mmol of benzylidene malononitrile, ethyl propiolate, dimethylacetylene dicarboxy‐ late, diethyl fumarate or diethylacetylene dicarboxylate was dissolved in 30 mL absolute ethanol in the presence of catalytic amount 1 mL of piperidine and was then refluxed for 6 h. After cooling, solid mixture was collected and recrystal‐ lized from ethanol. The %yield and melting point were calculated for the solid dry product. 2.3.2. Method B (Ultrasound irradiation) Independent mixture of same reaction components was dissolved in 30 mL absolute ethanol, in the presence of catalytic amount 1 mL of piperidine and then the reaction mixture was sonicated in MKC6, Guyson ultrasonic bath (Model‐MKC6, operating frequency 38 kHz +/‐ 10% and an output power of 110 Watts) for 3 hr at 80 °C. The hot reaction mixture was filtrated and washed with ethanol. The filtrate was concentrated and the solid product was collected and recrystallized from ethanol. 2.3.3. Method C (Microwave heating) Microwave‐assisted reactions were performed on a domestic 80 P instrument. The same procedure as described in method A and B was repeated under neat condition and was set for 2‐5 min. The solid product was collected after cooling and crystallization from ethanol while the %yield was calculated and compared with the previous methods. 2.3.4. Method D (Q‐tube) The same procedure as described in method A and B were sequentially added in a 35 mL Q‐tube pressure tube under neat condition, 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 140 °C. After about 10 min, the reaction mixture was monito‐red by TLC and GC/MS and stopped. The hot reaction mixture was filtrated and washed with ethanol and crystallization from ethanol while the %yield was calculated and compared with the previous methods (Scheme 2). 2‐Amino‐3‐(phenyldiazenyl)pyrazolo[1,5‐a]pyrimidin‐5‐ (4H)‐one (19): Color: Yellow. % Yields: Method A (85), Method B (82), Method C (60), and Method D (90). M.p.: 268‐270 °C. FT‐IR (KBr, , cm‐1): 3416, 3277 (NH2), 3179 (NH), 1651 (CO). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 5.96 (d, 1H, J = 7.6 Hz, CH5), 6.64 (s, 2H, NH2), 7.36 (t, 1H, J = 7.2 Hz, Ar‐H), 7.48 (t, 2H, J = 8.0 Hz, Ar‐H), 7.90 (d, 2H, J = 7.6 Hz, Ar‐H), 8.26 (d, 1H, J = 8.0 Hz, CH6), 12.90 (br. s, 1H, NH). 13C NMR (100 MHz, DMSO‐d6, δ, ppm): 104.31, 112.34, 121.49, 128.65, 128.92, 138.57, 150.84, 152.84, 160.20. MS (EI, m/z (%)): 255 (M+1, 15), 254 (M+, 100), 177 (43). HRMS (EI, m/z) calcd. for C12H10N6O, 254.0911; found 254.0914. Methyl 2‐amino‐7‐oxo‐3‐(phenyldiazenyl)‐4,7‐dihydropyra zolo[1,5‐a]pyrimidine‐5‐carboxylate (24): Color: Brown. % Yields: Method A (75), Method B (84), Method C (55), and Method D (80). M.p.: 250‐252 °C. FT‐IR (KBr, , cm‐1): 3423, 3271 (NH2), 3184 (NH), 1659 (CO), 1726 (COOH). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 3.94 (s, 3H, OCH3), 6.33 (s, 1H, CH6), 6.80 (s, 2H, NH2), 7.38 (t, 1H, J = 6.8 Hz, Ar‐H), 7.49 (t, 2H, J = 8.0 Hz, Ar‐H), 7.92 (d, 2H, J = 7.6 Hz, Ar‐H), 13.175 (br. s, 1H, NH). 13C NMR (100 MHz, DMSO‐d6, δ, ppm): 53.63, 104.17, 112.29, 120.66, 121.64, 128.81, 128.98, 139.56, 150.88, 152.71, 160.09. MS (EI, m/z (%)): 313 (M+1, 18), 312 (M+, 100), 77 (67). HRMS (EI, m/z) calcd. for C14H12N6O3, 312.0965; found 312.0965. Ethyl 2‐amino‐7‐oxo‐3‐(phenyldiazenyl)‐4,7‐dihydropyra zolo[1,5‐a]pyrimidine‐5‐carboxylate (29): Color: Brown. % Yields: Method A (70), Method B (78), Method C (66), and Method D (80). M.p.: 285‐286 °C. FT‐IR (KBr, , cm‐1): 3392, 3291 (NH2), 3182 (NH), 1733 (COOH), 1616 (CO). 1H NMR (600 MHz, DMSO‐d6, δ, ppm): 1.39 (t, 3H, J = 7.2 Hz, CH3), 4.39 (q, 2H, J = 7.2 Hz, CH2), 6.31 (s, 1H, CH6), 6.77 (s, 2H, NH2), 7.37 (t, 1H, J = 7.2 Hz, Ar‐H), 7.49 (t, 2H, J = 8.4 Hz, Ar‐H), 7.91 (d, 2H, J = 7.8 Hz, Ar‐H), 13.14 (br. s, 1H, NH). 13C NMR (150 MHz, DMSO‐d6, δ, ppm): 62.81, 112.26, 121.59 128.92, 139.71, 150.85, 152.67, 159.45. MS (EI, m/z (%)): 327 (M+1, 17), 326 (M+, 100), 249 (40). HRMS (EI, m/z) calcd. for C15H14N6O3, 326.1122; found 326.1122. 2,7‐Diamino‐5‐phenyl‐3‐(phenyldiazenyl)pyrazolo[1,5‐a] pyrimidine‐6‐carbonitrile (33): Color: Dark orange. % Yields: Method A (68), Method B (73), Method C (65), and Method D (76). M.p.: 230‐232 °C. FT‐IR (KBr, , cm‐1): 3465, 3438 (NH2), 3324, 3289 (NH2), 2218 (CN), 1642 (C=N). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 7.13 (s, 2H, NH2), 7.38 (t, 1H, J = 7.2 Hz, Ar‐ H), 7.50 (t, 2H, J = 7.6 Hz, Ar‐H), 7.57‐7.60 (m, 3H, Ar‐H), 7.81 (d, 2H, J = 7.6 Hz, Ar‐H), 7.88‐7.89 (m, 2H, Ar‐H), 8.61 (br. s, 2H, NH2). 350 AlMarzouq et al. / European Journal of Chemistry 7 (3) (2016) 347‐351 Table 1. The % yield products and the reaction time of pyrazolo[1,5‐a]pyrimidine derivatives by using different methods. Method Product (19) Product (24) Product (29) Product (33) Time Yield% Time Yield% Time Yield% Time Yield% A 6 hr 85 7 hr 75 7 hr 70 5 hr 68 B 3 hr 82 4 hr 84 4 hr 78 3 hr 73 C 1 min 60 1 min 55 4 min 66 2 min 65 D 5 min 90 10 min 80 30 min 80 5 min 76 Scheme 3 NH N N H2N NPh HN COOEt N N N H2N NPh NH2 COOEt 28 26 29 N H N N N H2N NPh COOEt COOEt O COOEt + 25 N H N N N H2N COOEt NPh 27 O COOEt EtOOC 4 N N N NH H2N NH2 Ph Scheme 4 13C NMR (100 MHz, DMSO‐d6, δ, ppm): 75.45, 116.15, 116.53, 121.25, 128.31, 128.66, 128.86, 129.12, 130.28, 137.22, 146.21, 148.87, 152.09, 152.79, 160.93. MS (EI, m/z (%)): 355 (M+1, 20), 354 (M+, 100), 277 (48). HRMS (EI, m/z) calcd. for C19H14N8, 354.1336; found 354.1337. 3. Results and discussion Compound 4 reacted with ethyl propiolate (15) utilizing either conventional heating (method A), ultrasound (method B), microwave heating (method C), or heating at 140 °C in Q‐ tube (method D). The same product was obtained in each case and reaction times as well as yields are listed in Table 1. The Mass spectra of the product indicated that addition followed by ethanol elimination occurred. Thus, structure 19 or isomeric 17 maybe postulated. However, 1H NMR of the product leads to exclude formation of isomeric 17. It showed pyrimidine protons at δ 7.90 and δ 8.29 ppm appeared as two doublets with J = 7.6, 8.0 Hz. If the product was isomeric 17 then one of their pyrimidine protons should have appeared as quartet (Scheme 2). Reacting compound 4 with dimethylacetylene dicarboxy‐ late (20) afforded compound 24 rather than isomeric 22. It is assumed that initially adduct compound 21 or 23 is formed and cyclize to compound 22 or 24. Possible formation of compound 22 was also excluded. Based on 1H NMR that revealed proton at C‐6 as singlet at δ 6.33 ppm. If the product is isomeric 22, it should appear at a lower field (≂ 7.9 ppm) (Scheme 3). Similarly, reaction of compound 4 with ethyl fumarate (25) afforded compound 29 rather than compound 27 via intermediacy of compound 28 (Scheme 4). Again, results of utilizing methods (A‐D) are tabulated in Table 1. Compound 4 were reacted with benzylidenemalononitrile (11) initially following literature procedure (method A), then utilizing ultrasound irradiation (method B), microwave heating (method C) and in a Q‐tube (method D) were gave us compound 33 rather than compound 31 (Scheme 5). We confirm the structure of compound 33 for the reaction product, based on 1H NMR spectra, that revealed the amino function at C‐7 at δ = 8.61 ppm which is downfield shifted by the anisotropic effect of pyrazole ring nitrogen. If the product is compound 31 it will appear at δ ≃ 5.8 ppm and (method D) gave a good yield with a record reaction time (Table 1). AlMarzouq et al. / European Journal of Chemistry 7 (3) (2016) 347‐351 351 N N N H2N N Ph NH2 30 32 31 N N N N H2N NPh NH2 Ph + 11 N N N N H2N NH2 NPh 33 Ph CN CN Ph NH N N H2N N Ph HN CN CN Ph CN CN 4 N N N NH H2N NH2 Ph C H C CN CN Ph Scheme 5 4. Conclusions 1. As regards in new rout of green chemistry, using new technique (Q‐tube), it is a logical outcome after several researches and comparison with several old methods, that an improvement of the reactions yields with a record time was achieved. 2. Pyrazole compounds can provide privileged scaffolds for the generation of target compounds for biological and pharmacological activities. 3. Utility of Q‐tube compering to microwaves, and ultrasound irradiation as green energy routes offers advantageous features such as good yield. 4. The method of Q‐tube represents a promising benign route to replace many conventional basic methods which can encounter many environmental problems. 5. Utility of Q‐tube method showed acceleration of several reactions in better way compared to microwave (MW) and ultrasound (US) methods. 6. Sealed tube is the key for all benefits (like short reaction time). Microwave is just a heating source, no impact on reactions. 7. For sealed tube, oil bath provided better results than microwave. Oil bath provides uniform heating while microwave could cause over heating due to its nature, which results in dark decomposed reaction mixture. Acknowledgements The authors are grateful to Kuwait University, Analytical Analab/SAF facilities provided by General Facility‐Science (GF‐ S) (Project No: GS 01/01, GS 01/03, GS 01/05, GS 02/10 & GS 03/08). Also, deep thankful to Prof. Dr. Mohamed Hilmy Elnagdi for his continual guidance during performing this work. References [1]. Elnagdi, M. H.; Abd Allah, S. O. J. Prakt. Chem. 1973, 315, 1009‐1016. [2]. Braun, H. J. Ger. Offen. 1998, DE 1996143059. [3]. Sener, N.; Sener, I.; Yavuz, S.; Karci, F. Asian J. 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