Received: 16 October 2017; Accepted: 29 November 2017; Published: 1 December 2017

Transcription

1 molecules Article Multi Component Reactions under Increased Pressure: On Mechanism Formation Pyridazino[5,4,3-de][1,6]naphthyridine Derivatives by Reaction Malononitrile, Aldehydes and 2-Oxoglyoxalarylhydrazones in Q-Tubes Majdah A. AL-Johani 1, Khadijah M. Al-Zaydi 1, *, Sameera M. Mousally 1, Norah F. Alqahtani 1, Noha Hilmy Elnagdi 2 and Mohamed H. Elnagdi 3 1 Department Chemistry, Faculty Sciences AL Faisaliah, King Abdulaziz University, Jeddah, P.O. Box 50918, Jeddah 21533, Saudi Arabia; moon98.1@hotmail.com (M.A.A.); smousally@kau.edu.sa (S.M.M.); Nalqahtani00123@kau.edu.sa (N.F.A.) 2 Department Organic Chemistry, Faculty Pharmacy, Modern University for Technology and Information, Cairo, P.O. Box 12518, Cairo 11511, Egypt; elnagdinoha@yahoo.com 3 Faculty Science, Cairo University, Cairo, P.O. Box 12613, Cairo 11511, Egypt; m.h.elnagdi@outlook.com * Correspondence: alzaydi_kh@yahoo.com; Tel.: Received: 16 Ocber 2017; Accepted: 29 November 2017; Published: 1 December 2017 Abstract: Efficient synsis phenanthridin-6(5h)-one derivatives 12a n in a four-component reaction hydrazone, aromatic s and in Q-Tubes is reported. The results showed methodology has advantage being a one-pot synsis tricyclic systems in good yields. Potential routes leading formation compounds 12 are discussed. The structures synsized compounds could be unequivocally established via X-ray crystal structure determination and spectroscopic methods. Keywords: X-ray crystallography; arylhydrazonals; 2-amino-1,1,3-propenetricarbonitrile; pyridazines; negative activation volume 1. Introduction The considerable biological and medicinal activities pyridazines has stimulated considerable research on efficient synses se derivatives in past years [1 4]. Elnagdi et al. reported synsis 2-amino-1,4-dihydropyridazine, an isoelectronic derivative 1,4-dihydropyrimidines established biological activities [5 8], via am combination arylhydrazones 1a and α,β-unsaturated nitriles 2 [9] or by reacting a mixture 1, 4 and 5 in one pot (Scheme 1). Subsequent studies [10,11] on this novel route revealed however it is a limited scope as reaction products proved be dependent on nature reacting aryl hydrazones. Multicomponent reaction 1a c α,β-unsaturated nitriles 2 in presence a base has been reported yield 3, while reaction 1f 2 in basic medium afforded new substituted pyrazolo[4,3-5,6]pyrimido[2,1-a]phthalazine-9-carbonitriles ring system 7 [12] (Scheme 1). Microwave energy has been reported be effective in synsis small molecules in many our previous works [13 16]. However, we noted microwaves technology is expensive scale up [17], in contrast using Q-Tube pressure reacrs, which proved accelerate reactions negative activation volume in a more optimal and safer manner, compared microwaves [18]. Molecules 2017, 22, 2114; doi: /molecules

2 Molecules 2017, 22, Molecules 2017, 22, 22, Scheme The reactivity aryl hydrazones 1 wards α,β-functionally substituted cinnamonitriles. Scheme 1. The reactivity aryl hydrazones wards α,β-functionally substituted cinnamonitriles. Our research group has previously reported extensively on use Q-Tubes synsize such Our compounds research group but has reaction previously conditions reported in extensively se published on works use Q-Tubes had many limitations synsize such compounds altered nature but reaction synsized conditions products in se published [19,20] (Scheme works 2). had The many human limitations urge find altered cures for nature challenging diseases synsized and improve products human [19,20] (Scheme life leads 2). organic The human chemists urge be find a cures continuous for challenging quest diseases develop and novel improve polyfunctional human life heterocycles, leads organic as well chemists as developing be a new continuous economical quest develop and greener novel polyfunctional heterocycles, as well as developing new economical and greener technologies. technologies. Considering promising biological activity new compounds 12 where ring Considering promising biological activity new compounds 12 where ring system combines system combines pyridazine and napthyridine rings, both vast biological activities [21 24], we pyridazine napthyridine rings, both vast biological activities [21 24], we sought expand sought expand this work prove method proposed for synsis se novel this work prove method proposed for synsis se novel compounds is a general compounds is a general one by making more examples. Moreover this work has led proposal one by making more examples. Moreover this work has led proposal a plausible reaction a plausible reaction mechanism would clarify and lead way for any furr work such mechanism would clarify and lead way for any furr work on such new ring systems. new ring systems. Scheme Novel synsis tricyclic system 11 by reacting ethyl-3-oxo-2-(2-phenylhydrazono) pentanoate (8a) (9) and aromatic derivatives in in a Q-Tube Results Results The The reactions reactions in in Q-Tubes Q-Tubes (cf. (cf. Figure Figure 1) 1) at at C and C and 20 psi 20 psi 2-oxo-2-arylhydrazonals 2-oxo-2-arylhydrazonals 1a,b 1a,b aromatic aromatic s s 10a g 10a g and and (9) in dioxane (9) in dioxane in presence in presence piperidine piperidine afforded afforded compounds compounds 12a n. The 12a n. tricyclic The tricyclic systems systems 12 are formed 12 are formed in 72 85% in 72 85% yield (Scheme yield (Scheme 3, Table 3, Table 1). The 1). The structure structure reaction reaction products products could could be be established established be be pyridazino[5,4,3-de][1,6]naphthyridine pyridazino[5,4,3-de][1,6]naphthyridine derivatives 12a n via spectroscopic methods (available in supplementary materials) as well as X-ray crystal structure determination products 12a, 12m and 12n (Figures 1 3).

3 Molecules 2017, 22, derivatives 12a n via spectroscopic methods (available in supplementary materials) as well as 2017, 22, X-rayMolecules crystal2017, structure 22, 2114 determination products 12a, 12m and 12n (Figures 1 3). 10 Scheme 3. A new reaction path for reaction hydrazones Scheme 3. new reaction path for reaction hydrazones Schemeand 3. As. new reaction path for reaction hydrazones and s. and s. Table Table Table Synsis 1. Synsis pyridazino[5,4,3-de][1,6]naphthyridine derivatives pyridazino[5,4,3-de][1,6]naphthyridine derivatives 12a n. 12a n. 12a n. Entry R Ar Yield % Time (min) Entry Entry R Ar Ar Yield Yield % Time (min) Time (min) 12a H Ph a Ph b 12a H Ph 4-ClC6H b 4-ClC6H c 12b H 4-ClC 2-ClC6H4 6 H c 2-ClC6H d 12c H 2-ClC 6 H CH3C6H d 4-CH3C6H4 12d 4-CH e 3 C 6 H H 2-CH3C6H e 12e 2-CH2-CH3C6H4 3 C 6 H f H 4-O2NC6H f 12f 4-O 2 4-O2NC6H4 6 H g 12g 12g H 2-furyl 2-furyl 2-furyl h CH3 12h 12h CH3 3 Ph Ph Ph j 12j 12j CH3 CH3 3 4-ClC 4-ClC6H4 4-ClC6H4 6 H k 12k 12k CH3 CH3 3 4-CH4-CH3C6H4 4-CH3C6H4 3 C 6 H l 12l CH3 12l CH3 3 2-CH2-CH3C6H4 2-CH3C6H4 3 C 6 H m 12m CH3 12m 3 4-O 2 4-O2NC6H4 NC 6 H CH3 4-O2NC6H n 12n CH3 CH 3 2-furyl 2-furyl n CH3 2-furyl Figure 1. X-ray crystallographic structure compound 12a [25]. Figure 1. X-ray crystallographic structure compound 12a [25]. Figure 1. X-ray crystallographic structure compound 12a [25].

4 Molecules 2017, 22, 2114 Molecules 2017, 22, Molecules 2017, 22, Figure 2. X-ray crystallographic structure compound 12m [26]. Figure Figure X-ray X-ray crystallographic crystallographic structure structure compound compound 12m 12m [26]. [26]. Figure 3. X-ray crystallographic structure compound 12n [27]. Figure 3. X-ray crystallographic structure compound 12n [27]. Figure 3. X-ray crystallographic structure compound 12n [27]. 3. Discussion 3. Discussion 3. Discussion Two mechanistic pathways seem possible (Scheme 4): initial yield dimer Two mechanistic 13, pathways condenses seem possible acyl (Scheme carbonyl 4): initial 14 cyclizes form 15 (route A) yield Two [19]. dimer mechanistic This route 13, could pathways readily condenses seem be eliminated possible acyl (Scheme as in carbonyl 4): initial our hands 14 cyclizes could not form be dimerized 15 (route yield dimer under A) [19]. 13, This reported route condenses could conditions readily moreover be eliminated acyl carbonyl when as it in is our considered hands 14 cyclizes this could form not 15 (route be it dimerized A) [19]. This probably impossible under route could in reported readily absence conditions be eliminated ethoxide moreover as in or sodium when our hands it hydroxide is considered which could are this thought not be dimerized necessary it probably under for impossible reported in conditions absence moreover [27]. ethoxide when it or is sodium considered hydroxide this which are thought it probably necessary impossible for in absence Moustafa et ethoxide or sodium al. also reported [27]. hydroxide which are thought necessary for dimer 13 alone reacts ir arylhydrazones 1a,b Moustafa [27]. pyridazino[5,4,3-de][1,6]naphthyridine et al. also reported dimer derivatives, 13 alone reacts not condensed ir arylhydrazones pyridazine 1a,b derivatives. Moustafa pyridazino[5,4,3-de][1,6]naphthyridine et al. also reported dimer 13 alone Thus, it is almost certain initial derivatives, reacts step leading not ir condensed arylhydrazones formation 1a,b pyridazine pyridazino[5,4,3-de][1,6]naphthyridine 12 is condensation derivatives. Thus, it is almost (9) certain derivatives, acyl carbonyl not initial condensed 18. The step product leading pyridazine 19 can formation derivatives. eir cyclize 12 is Thus, in it 20 condensation is almost certain and 21 (route initial C) or condense (9) step leading acyl an carbonyl formation aromatic 18. The 12 product is condensation give 19 can 22 and eir 23 cyclize (route D). in (9) Neir 20 and acyl route carbonyl 21 C or (route 18. The D can C) product completely or condense 19 can be ruled an eir out, aromatic cyclize although in 20 and we believe give and (route aromatic C) 23 or condense (route D). condenses Neir an aromatic route initially C or D can 19 completely give 22 and subsequent be ruled 23 reactions out, (route although D). Neir lead 22 we believe route C or reacts D can aromatic completely be ruled (9) condenses out, although form 23 initially we which believe cyclizes 19 subsequent aromatic final product reactions 12 (Scheme lead condenses 4). 22 initially reacts 19 subsequent reactions (9) form lead 23 which 22 cyclizes reacts final product 12 (Scheme (9) 4). form 23 which cyclizes final product 12 (Scheme 4).

5 Molecules 2017, 22, Molecules 2017, 22, Scheme The proposed mechanism for formation pyridazino[5,4,3-de][1,6]naphthyridine derivatives 12a n Materials and Methods 4.1. General Information Q-tube assisted reactions were performed in a Q-tube safe pressure reacr from Q Labtech (East Lyme, CT 06333, CT, USA, equipped aa cap/sleeve, pressure adapter (120 psi), needle adapter/needle, borosilicate glass glass tube, tube, Teflon Teflon septum, septum, and catch and bottle. catch All bottle. reactions All were reactions monired were by monired using TLC by using 1:1 TLC ethyl acetate-petroleum 1:1 ethyl acetate-petroleum er as eluent er and as eluent were and carried were out carried until out starting until materials starting materials were completely were completely consumed. consumed. Melting points Melting are reported points are uncorrected reported uncorrected and were determined and were determined a Sanyo (Gallenkamp, a Sanyo (Gallenkamp, Osaka, Japan) Osaka, instrument. Japan) instrument. Infrared spectra Infrared were spectra recorded were using recorded KBr pellets using and KBr apellets FT IR 6300 and a instrument FT IR 6300 (Jasco, instrument Tokyo, Japan) (Jasco, and Tokyo, absorption Japan) bands absorption are reportedbands in cm 1 are. 1 reported H- and 13 in C-NMR cm 1. 1 spectra H- and were 13 C-NMR determined spectra by were using determined a DPX instrument by using (Bruker, a DPX Billerica, instrument MA, (Bruker, USA) at Billerica, 400 MHz MA, or USA) 600 MHz at 400 formhz 1 H-NMR or 600 and MHz 100 for MHz 1 H-NMR for 13 C-NMR and 100 and MHz eir for CDCl 13 C-NMR 3 or and DMSO-d eir 6 CDCl3 or DMSO-d6 solutions TMS as internal standards. Chemical shifts are reported in ppm. Mass spectra and accurate mass measurements were made using a GCMS DFS spectrometer

6 Molecules 2017, 22, solutions TMS as internal standards. Chemical shifts are reported in ppm. Mass spectra and accurate mass measurements were made using a GCMS DFS spectrometer (Thermo, Bremen, Germany) EI (70 EV) mode. X-ray crystallographic structure determinations were performed by using Rapid II (Rigaku, Tokyo, Japan) and X8 Prospecr (Bruker, Karlsruhe, Germany) single crystal X-ray diffracmeters. All X-ray crystal structure data can be obtained free charge from Cambridge Crystallographic Data Centre [26 28] via The data and material are available in Supplementary material and manuscript. Supplementary material is attached as PDF format and submitted along manuscript General Procedures for Q-Tube-Assisted Synsis 12a n 2-Oxo-2-arylhydrazonals 1a,b (0.01 mol), aromatic s 13a g (0.01 mol) and (9) was 9 before (0.02 mol) in presence piperidine (1 ml) and dioxin (20 ml) as solvent were sequentially added in a 35 ml Q-tube pressure tube, furnished by Q Labtech. A Teflon septum was placed on p tube, and an appropriate cap was used. The mixture was heated in an oil bath at 150 C. After about 60 min, reaction mixture was monired by TLC. The mixture was cooled and poured in ice-water. The solid was collected by filtration and purified by column chromagraphy and crystallized from ethanol. 8-Amino-1,5-diphenyl-1H-pyridazino[5,4,3-de][1,6]naphthyridine-7-carbonitrile (12a). Dark yellow crystals, Yield 85%; m.p C; Anal. Calcd. for C 22 H 14 N 6 (362.13): C, 72.92; H, 3.89; N, Found: C, 72.83; H, 3.79; N, EI-HRMS: m/z = (MH + ); C 22 H 14 N 6 requires: m/z = (MH + ); 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 7.06 (br, 2H, NH 2, D 2 O exchangeable), (m, H, Ph-H, CH), (m, 2H, Ph-H), 8.38 (s, 1H, CH); 13 C-NMR (100 MHz, DMSO-d 6 ): δ = 162.0, 161.2, 154.5, 150.9, 141.7, 138.7, 137.8, 133.2, 130.3, (2C), (2C), 128.1, (2C), (2C), 116.8, 108.8, 104.6, MS: m/z (%) (M +, 100), 334 (10), 181 (10), 77 (5). 8-Amino-5-(4-chlorophenyl)-1-phenyl-1H-pyridazino[5,4,3-de][1,6]naphthyridine-7-carbonitrile (12b). Green crystals, yield 75%; m.p C; Anal. Calcd. for C 22 H 13 ClN 6 (396.06): C, 66.59; H, 3.30; N, Found: C, 66.70; H, 3.35; N, EI-HRMS: m/z = (MH + ); C 22 H 13 N 6 35 Cl requires: m/z (MH + ); 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 7.10 (br, 2H, NH 2, D 2 O exchangeable), (m, 8H, Ph-H, CH), (m, 2H, Ph-CH), 8.38 (s, 1H, CH); 13 C-NMR (100 MHz, DMSO-d 6 ): δ = 162.1, 160.0, 154.6, 151.0, 141.7, 138.7, 136.7, 133.4, 130.3, (2C), (2C), 128.2, (2C), (2C), 118.0, 109.1, 104.6, MS: m/z (%) (M +, 100), 368 (10), 198 (10), 166 (5), 77 (5). 8-Amino-5-(3-chlorophenyl)-1-phenyl-1H-pyridazino[5,4,3-de][1,6]naphthyridine-7-carbonitrile (12c). Green crystals, yield 80%; m.p C; Anal. Calcd. for C 22 H 13 ClN 6 (396.06): C, 66.59; H, 3.30; N, Found: C, 66.57; H, 3.33; N, EI-HRMS: m/z = (MH + ); C 22 H 13 N 6 35 Cl requires: m/z = (MH + ); 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 7.11 (br, 2H, NH 2, D 2 O exchangeable), 7.27 (s, 1H, CH), (m, 9H, Ph-H), 8.45 (s, 1H, CH); 13 C-NMR (100 MHz, DMSO-d 6 ): δ = 162.2, 162.0, 154.6, 151.1, 141.7, 138.8, 138.5, 132.4, 131.4, 131.0, 130.6, (2C), 128.8, 128.2, 127.4, (2C), 116.8, 108.9, 108.8, MS: m/z (%) (M +, 100), 361 (15), 334 (5), 198 (10), 166 (5), 77 (5). 8-Amino-1-phenyl-5-p-lyl-1H-pyridazino[5,4,3-de][1,6]naphthyridine-7-carbonitrile (12d). Faint green crystals, yield 77%; m.p C; Anal. Calcd. for C 23 H 16 N 6 (376.14): C, 73.39; H, 4.28; N, Found: C, 73.34; H, 4.30; N, EI-HRMS: m/z = (MH + ); C 23 H 16 N 6 requires: m/z = (MH + ); 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 2.39, 2.51 (s, 3H, CH 3 ), 7.05 (br, 2H, NH 2, D 2 O exchangeable), (m, 8H, Ph-H, CH), (m, 2H, Ph-H), 8.36 (s, 1H, CH); 13 C-NMR (100 MHz, DMSO-d 6 ): δ = 162.2, 161.2, 154.4, 150.9, 141.7, 140.2, 138.8, 135.1, 133.2, (2C), (2C), 128.1, (2C), (2C), 116.9, 108.7, 104.2, 73.3, MS: m/z (%) (M +, 100), 348 (10), 188 (10), 77 (5). 8-Amino-1-phenyl-5-m-lyl-1H-pyridazino[5,4,3-de][1,6]naphthyridine-7-carbonitrile (12e). Green crystals, yield 73%; m.p C; Anal. Calcd. for C 23 H 16 N 6 (376.14): C, 73.39; H, 4.28; N, Found: C,

7 Molecules 2017, 22, ; H, 4.27; N, EI-HRMS: m/z = (MH + ); C 23 H 16 N 6 requires: m/z = (MH + ); 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 2.43,2.51 (s, 3H, CH 3 ), 7.07 (br, 2H, NH 2, D 2 O exchangeable), 7.18 (s, 1H, CH), (m, 9H, Ph-H), 8.40 (s, 1H, CH); 13 C-NMR (100 MHz, DMSO-d 6 ): δ = 165.2, 162.0, 154.3, 151.1, 141.7, 139.6, 138.7, 135.8, 133.7, 130.8, 129.3, 128.9, (2C), 128.1, (2C), 125.9, 116.9, 108.3, 108.2, 73.3, MS: m/z (%) 376 (M +, 50), 375 (100), 348 (10), 255 (10), 187 (10), 77 (5). 8-Amino-5-(4-nitrophenyl)-1-phenyl-1H-pyridazino[5,4,3-de][1,6]naphthyridine-7-carbonitrile (12f). Dark brown crystals, yield 82%; m.p C; Anal. Calcd. for C 22 H 13 N 7 O 2 (407.11): C, 64.86; H, 3.22; N, Found: C, 64.75; H, 3.10; N, EI-HRMS: m/z = (MH + ); C 22 H 13 O 2 N 7 requires: m/z = (MH + ); 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 7.18 (br, 2H, NH 2, D 2 O exchangeable), (m, 5H, Ph-H, CH), 7.93, (d, 1H, CH-pyridazine), (m, 4H, Ph-H, CH), 9.20, 9.41 (s, 1H, CH). MS: m/z (%) (M +, 100), 361 (20), 334 (10), 180 (10), 77 (5). 8-Amino-5-(furan-2-yl)-1-phenyl-1H-pyridazino[5,4,3-de][1,6]naphthyridine-7-carbonitrile (12g). Dark green crystals, yield 86%; m.p C; Anal. Calcd. for C 20 H 12 N 6 O (352.11): C, 68.18; H, 3.43; N, Found: C, 68.21; H, 3.52; N, EI-HRMS: m/z = (MH + ); C 20 H 12 O 1 N 6 requires: m/z = (MH + ); 1 H-NMR (400 MHz, DMSO-d 6 ): δ = (m, 1H, furyl-h), 7.05 (br, 2H, NH 2, D 2 O exchangeable), (m, 8H, Ph-H, furyl-h, CH), 8.42 (s, 1H, CH); 13 C-NMR (100 MHz, DMSO-d 6 ): δ = 162.0, 154.6, 153.2, 152.7, 150.8, 145.6, 141.7, 138.6, 133.2, (2C), 128.2, (2C), 116.8, 112.7, 11.8, 108.6, 102.7, MS: m/z (%) (M +, 100), 324 (5), 176 (10), 77 (5). 8-Amino-4-methyl-1,5-diphenyl-1H-pyridazino[5,4,3-de][1,6]naphthyridine-7-carbonitrile (12h). Yellow crystals, yield 83%; m.p C; Anal. Calcd. for C 23 H 16 N 6 (376.14): C, 73.39; H, 4.28; N, Found: C, 73.35; H, 4.15; N, EI-HRMS: m/z = (MH + ); C 23 H 16 N 6 requires: m/z = (MH + ); 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 2.34, 2.50 (s, 3H, CH 3 ), 6.95 (br, 2H, NH 2, D 2 O exchangeable), (m, 10H, Ph-H, CH), 8.56 (s, 1H, CH); 13 C-NMR (100 MHz, DMSO-d 6 ): δ = 164.5, 161.6, 152.3, 150.6, 141.8, 140.0, 136.9, 131.0, (2C), (2C), 128.5, 128.2, (2C), (2C), 117.1, 114.1, 108.9, 72.6, MS: m/z (%) (M +, 100), 368 (10), 348 (5), 255 (5), 188 (10), 97 (10), 57 (5). 8-Amino-5-(4-chlorophenyl)-4-methyl-1-phenyl-1H-pyridazino[5,4,3-de][1,6]naphthyridine-7-carbonitrile (12j). Dark yellow crystals, yield 78%; m.p C; Anal. Calcd. for C 23 H 15 ClN 6 (410.1): C, 67.24; H, 3.68; N, Found: C, 67.27; H, 3.56; N, EI-HRMS: m/z = (MH + ); C 23 H 15 N 6 35 Cl requires: m/z = (MH + ); 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 2.35, 2.50 (s, 3H, CH 3 ), 6.90 (br, 2H, NH 2, D 2 O exchangeable), (m, 9H, Ph-H, CH), 8.58 (s, 1H, CH); 13 C-NMR (100 MHz, DMSO-d 6 ): δ = 163.8, 162.1, 156.4, 151.1, 142.3, 139.4, 137.3, 134.0, 132.5, 131.7, (2C), (2C), (2C), (2C), 117.2, 114.8, 109.7, 73.5, MS: m/z (%) (M +, 100), 374 (10), 346 (5), 255 (5), 205 (5), 187 (10), 173 (5), 97 (5), 77 (5). 8-Amino-4-methyl-1-phenyl-5-p-lyl-1H-pyridazino[5,4,3-de][1,6]naphthyridine-7-carbonitrile (12k). Dark orange crystals, yield 80%; m.p C; Anal. Calcd. for C 24 H 18 N 6 (390.16): C, 73.83; H, 4.65; N, Found: C, 73.88; H, 4.59; N, EI-HRMS: m/z = (MH + ); C 24 H 18 N 6 requires: m/z = (MH + ); 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 2.36 (s, 3H, CH 3 ), 2.41 (s, 3H, CH 3 ), 6.93 (br, 2H, NH 2, D 2 O exchangeable), (m, 9H, Ph-H, CH), 8.56 (s, 1H, CH); 13 C-NMR (100 MHz, DMSO-d 6 ): δ = 163.9, 161.6, 152.4, 150.7, 141.8, 140.2, 137.2, (2C), (2C), (2C), 127.1, (2C), 129.1, 124.5, 119.1, 114.8, 109.7, 72.6, 20.8, MS: m/z (%) (M +, 100), 375 (5), 269 (5), 187 (5), 77 (5). 8-Amino-4-methyl-1-phenyl-5-m-lyl-1H-pyridazino[5,4,3-de][1,6]naphthyridine-7-carbonitrile (12l). Yellow crystals, yield 72%; m.p C; Anal. Calcd. for C 24 H 18 N 6 (390.16): C, 73.83; H, 4.65; N, Found: C, 73.81; H, 4.68; N, EI-HRMS: m/z = (MH + ); C 24 H 18 N 6 requires: m/z = (MH + ); IR: 3489, 3336 (NH 2 ), 2200 (CN); 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 2.08 (s, 3H, CH 3 ), 2.11 (s, 3H, CH 3 ), 6.96 (br, 2H, NH 2, D 2 O exchangeable), (m, 9H, Ph-H, CH), 8.53 (s, 1H, CH); 13 C-NMR (100 MHz, DMSO-d 6 ): δ = 165.5, 161.5, 152.4, 150.7, 141.8, 139.8, 136.9, 134.8, 130.6, 130.0,

8 Molecules 2017, 22, (2C), (2C), (2C), (2C), 117.1, 114.7, 109.0, 72.6, 19.0, MS: m/z (%) (M +, 50), 375 (100), 346 (5), 255 (5), 195 (5), 187 (15), 173 (10), 129 (5), 77 (5). 8-Amino-4-methyl-5-(4-nitrophenyl)-1-phenyl-1H-pyridazino[5,4,3-de][1,6]naphthyridine-7-carbonitrile (12m). Dark yellow crystals, yield 82%; m.p C; Anal. Calcd. for C 23 H 15 N 7 O 2 (421.13): C, 65.55; H, 3.59; N, Found: C, 65.59; H, 3.63; N, EI-HRMS: m/z = (MH + ); C 23 H 15 O 2 N 7 requires: m/z = (MH + ); 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 2.37, 2.53 (s, 3H, CH 3 ), 6.82 (br, 2H, NH 2, D 2 O exchangeable), (m, 9H, Ph-H, CH), 8.58, 8.58 (s, 1H, CH); 13 C-NMR (100 MHz, DMSO-d 6 ): δ = 14.56, 49.5, 105, (2C), (2C), , (2C), (4C), , , , , ; MS: m/z (%) (M +, 100), 390 (15), 374 (25), 348 (10), 255 (5), 187 (10), 77 (5). 8-Amino-5-(furan-2-yl)-4-methyl-1-phenyl-1H-pyridazino[5,4,3-de][1,6]naphthyridine-7-carbonitrile (12n). Dark green crystals, yield 86%; m.p C; Anal. Calcd. for C 21 H 14 N 6 O (366.12): C, 68.84; H, 3.85; N, Found: C, 68.89; H, 3.78; N, EI-HRMS: m/z = (MH + ); C 21 H 14 O 1 N 6 requires: m/z = (MH + ); 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 2.50 (s, 3H, CH 3 ), (m, 1H, furyl-h), 6.91 (br, 2H, NH 2, D 2 O exchangeable), (m, 7H, Ph-H, furyl-h), 8.52 (s, 1H, CH); 13 C-NMR (100 MHz, DMSO-d 6 ): δ = 161.6, 153.0, 152.4, 152.2, 150.4, 145.1, 141.8, 136.8, 131.8, (2C), 128.2, (2C), 117.0, 114.3, 113.2, 112.0, 108.8, 72.3, MS: m/z (%) (M +, 100), 337 (5), 311 (5), 183 (5), 77 (10). 5. Conclusions Synsis 2-amino-1,4-dihydropyridazines by reacting arylhydrazonals, active methylene nitriles and aromatic s has been found very limited scope. We show here under pressure sequence this multicomponent reaction changes as initial step least activation volume predominates, and in this way a novel route pyridazino[5,4,3-de][1,6]naphthyridines could be developed. Our observations open route for discovering new multicomponent reactions under pressure, thus it is recommended expand this technique. Supplementary Materials: Supplementary Materials are available online. Acknowledgments: This project was funded by Deanship Scientific Research (DSR), King Abdulaziz University, Jeddah, under grant No. ( RG). The authors, refore, would like express ir deep gratitude DSR technical and financial support. Author Contributions: The main part work was carried out by Majdah A. AL-Johani, Sameera M. Mousally and Noha Hilmy Elnagdi, under direct supervision Khadijah M. Al-Zaydi and Norah F. Alqahtani. Conceptually work was designed by Mohamed H. Elnagdi, Khadijah M. Al-Zaydi and Norah F. Alqahtani. All authors read and approved final manuscript. Conflicts Interest: The authors declare y have no competing interests. References 1. Asif, M. Some Recent Approaches Biologically Active Substituted Pyridazine and Phthalazine Drugs. Curr. Med. Chem. 2012, 19, [CrossRef] [PubMed] 2. Singh, A.K.; Hegde, G.L.; Khanum, S.A.; Shashikanth, S. Synsis and Pharmacological Activity 4-Aryl-Thieno-(2,3-d)-Pyridazines. Indian J. Pharm. Sci. 2005, 67, Tucaliuc, R.A.; Cotea, V.V.; Niculaua, M.; Tuchilus, C.; Mantu, D.; Mangalagiu, I.I. New pyridazine fluorine derivatives: Synsis, chemistry and biological activity. Eur. J. Med. Chem. 2013, 67, [CrossRef] [PubMed] 4. Gao, Q.; Zhu, Y.; Lian, M.; Liu, M.; Yuan, J.; Yin, G.; Wu, A. Unexpected C C Bond Cleavage: A Route 3, 6-Diarylpyridazines and 6-Arylpyridazin-3-ones from 1,3-Dicarbonyl Compounds and Methyl Kenes. J. Org. Chem. 2012, 77, [CrossRef] [PubMed] 5. Kessler, S.N.; Wegner, H.A. One-Pot Synsis Phthalazines and Pyridazino-aromatics: A Novel Strategy for Substituted Naphthalenes. Org. Lett. 2012, 14, [CrossRef] [PubMed]

9 Molecules 2017, 22, Poschenrieder, H.; Stachel, H.-D. Synsis pyrrolo[3,4-c]pyridazines. J. Heterocycl. Chem. 1995, 32, [CrossRef] 7. Behbehani, H.; Ibrahim, H.M. Microwave-Assisted Synsis in Water: First One-Pot Synsis A Novel Class Polysubstituted benzo[4,5]imidazo[1,2-b]pyridazines via Intramolecular SNAr. RSC Adv. 2015, 5, [CrossRef] 8. Elnagdi, M.H.; Moustafa, M.S.; Sadek, K.U. Green Synsis Biologically Relevant Azoles and Azines Derivatives, 1st ed.; Lap Lambert Acadimic Publishing: Saarbrücken, Germany, 2014; p. 64. ISBN Ghozlan, S.A.S.; Abdelhamid, I.A.; Hassaneen, H.M.; Elnagdi, M.H. Studies Enamines and Azaenamines: A novel Efficient Route 6-amino-1,4-dihydropyridazines and ir Condensed Derivatives. J. Heterocycl. Chem. 2007, 44, [CrossRef] 10. Al-Mousawi, S.M.; Moustafa, M.S.; Abdelhamid, I.A.; Elnagdi, M.H. Reassignment Structures Condensation Products α-ke α -formylarylhydrazones Ethyl Cyanoacetate: A Novel Route ethyl 5-arylazo-2-hydroxynicotinates. Tetrahedron Lett. 2011, 52, [CrossRef] 11. Ackermann, L.; Gunnoe, T.B.; Habgood, L.G. Catalytic Hydroarylation Carbon-Carbon Multiple Bonds; Wiley-VCH Verlag Gmbh & Co. KGaA: Weinheim, Germany, 2017; pp ISBN Ghozlan, S.A.S.; Abdelmoniem, A.M.; Butenschon, H.; Abdelhamid, I.A. Discrepancies in The Reactivity Pattern Azaenamines wards Cinnamonitriles: Synsis Novel aza-steroid Analogues. Tetrahedron 2015, 71, [CrossRef] 13. Al-Zaydi, K.M. Microwave Assisted Synsis, Part 1: Rapid Solventless Synsis 3-Substituted Coumarins and Benzocoumarins by Microwave Irradiation Corresponding Enaminones. Molecules 2003, 8, [CrossRef] 14. Al-Zaydi, K.M.; Borik, R.M.; Elnagdi, M.H. Arylhydrazononitriles as Precursors 2-Substituted 1,2,3-triazoles and 4-amino-5-cyano-pyrazole Derivatives Utilizing Microwave and Ultrasound Irradiation. Green Chem. Lett. Rev. 2012, 5, [CrossRef] 15. Al-Zaydi, K.M.; Nhari, L.M.; Borik, R.M.; Elnagdi, M.H. Green Technologies in Organic Synsis: Self-Condensation Enamines, Enaminones and EnaminoestersUnder Microwave Irradiation in Ionic Liquid. Green Chem. Lett. Rev. 2010, 3, [CrossRef] 16. Al-Zaydi, K.M.; Borik, R.M.; Elnagdi, M.H. 2-Arylhydrazonopropanals as Building Blocks in Heterocyclic Chemistry: Microwave Assisted Condensation 2-Aryl-hydrazonopropanals Amines and Active Methylene Reagents. Molecules 2003, 8, [CrossRef] 17. Kappe, C.O.; Stadler, A. Microwaves in Organic and Medicinal Chemistry; John Wiley & Sons: Hoboken, NJ, USA, 2005; pp ISBN [CrossRef] 18. Kappe, C.O.; Dallinger, D.; Murphree, S.S. Practical Microwave Synsis for Organic Chemists Strategies; John Wiley & Sons: Hoboken, NJ, USA, 2009; pp ISBN [CrossRef] 19. Moustafa, M.S.; Al-Mousawi, S.M.; Abdelhamid, I.A.; Elnagdi, M.H. Use A Novel Multicomponent Reaction Under High Pressure for The Efficient Construction A New Pyridazino[5,4,3-de][1,6] naphthyridine Tricyclic System. RSC Adv. 2016, 93, [CrossRef] 20. Sadek, K.U.; Selim, M.A.;.Alnajjar, A.; Atallah, M.; Elnagdi, M.H. Multicomponent Reactions under Increased Pressure: On Reaction Arylhydrazonals, Aromatic Aldehydes and Malononitrile in Q-Tube. Chem. Eur. J. 2016, 7, [CrossRef] 21. Almansour, A.I.; Kumar, R.S.; Arumugam, R.; Basiri, A.; Kia, Y.; Ali, M.A. An Expedient Synsis, Acetylcholinesterase Inhibiry Activity, and Molecular Modeling Study Highly Functionalized Hexahydro-1,6-naphthyridines. BioMed Res. Int. 2015, 2015, 1 9. [CrossRef] [PubMed] 22. Raboisson, P.; Desjarlais, R.L.; Reed, R.; Lattanze, J.; Chaikin, M.; Many, C.L.; Tomczuk, B.E.; Marugan, J.J. Identification novel short chain 4-substituted indoles as potent alphavbeta3 antagonist using structure-based drug design. Eur. J. Med. Chem. 2007, 42, 334. [CrossRef] [PubMed] 23. Huang, X.; Chen, D.; Wu, N.; Zhang, A.; Jia, Z.; Li, X. The synsis and biological evaluation a novel series C7 non-basic substituted fluoroquinolones as antibacterial agents. Bioorg. Med. Chem. Lett. 2009, 19, [CrossRef] [PubMed] 24. Zeng, L.; Wang, Y.; Kazemi, R.; Xu, S.; Xu, Z.; Sanchez, T.W.; Yang, L.; Debnath, B.; Odde, S.; Xie, H. Repositioning HIV-1 Integrase Inhibirs for Cancer Therapeutics: 1,6-Naphthyridine-7-carboxamide as a Promising Scaffold Drug-like Properties. J. Med. Chem. 2012, 55, [CrossRef] [PubMed]

10 Molecules 2017, 22, CCDC Contains X-ray Structure Crystallographic Data for This Paper. Available online: (or from CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: ; CCDC Contains X-ray Structure Crystallographic Data for This Paper. Available online: (or from CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: ; CCDC Contains X-ray Structure Crystallographic Data for This Paper. Available online: (or from CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: ; Mittelbach, M. An improved and facile synsis 2-Amino-1,1,3-trycyanopropene. Monatsh. Chem. 1985, 116, [CrossRef] Sample Availability: Samples compounds 12a n are available from authors by authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under terms and conditions Creative Commons Attribution (CC BY) license (