untitled European Journal of Chemistry 6 (1) (2015) 84‐87 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2015 Atlanta Publishing House LLC ‐ All rights reserved ‐ Printed in the USA http://dx.doi.org/10.5155/eurjchem.6.1.84‐87.1149 European Journal of Chemistry Journal webpage: www.eurjchem.com Synthesis and antioxidant evaluation of some new pyridines Moustafa Ahmed Gouda 1,2,* and Mohamed Hamdy Helal 3,4 1 Chemistry Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt 2 Department of Chemistry, Faculty of Science and Arts, Taibah University, Ulla, 41411, Kingdom of Saudi Arabia 3 Department of Chemistry, Faculty of Arts and Science, Northern Border University, Rafha, 1321, Kingdom of Saudi Arabia 4 Department of Chemistry, Faculty of Science, Al‐Azhar University, Nasr City, Cairo, 11284, Egypt * Corresponding author at: Chemistry Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt. Tel.: +2.050.6432235. Fax: +2.050.2246781. E‐mail address: dr_mostafa_chem@yahoo.com (M.A. Gouda). ARTICLE INFORMATION ABSTRACT DOI: 10.5155/eurjchem.6.1.84‐87.1149 Received: 09 September 2014 Received in revised form: 08 October 2014 Accepted: 09 October 2014 Published online: 31 March 2015 Printed: 31 March 2015 One‐pot condensation of malononitrile (1), 4‐methylpentan‐2‐one (2), aryl carboxaldehyde (3a‐f) and ammonium acetate in ethanol afforded 2‐amino‐5‐isopropyl‐4‐(4‐aryl)‐6‐ methylnicotinonitriles (4a‐f). The antioxidant activity of the new synthesized compounds was evaluated and the result showed all compound exhibited weak anti‐oxidant activities. KEYWORDS Pyridine Malononitrile Nicotinonitrile Antioxidant activity Aryl carboxaldehyde 4‐Methylpentan‐2‐one Cite this: Eur. J. Chem. 2015, 6(1), 84‐87 1. Introduction Multicomponent coupling reactions (MCRs) have been frequently used by synthetic chemists as a facile means to generate molecular diversity from bifunctional substrates that react sequentially in an intermolecular fashion [1,2]. Devising such types of MCRs that achieve the formation of multiple bonds in a single operation is one of the major challenges in modern organic synthesis [3,4]. As such processes avoid time consuming and costly purification processes, as well as protection‐deprotection steps, they are inherently more environmentally benign and atom economic [5]. Many naturally occurring as well as synthetic compounds containing the pyridine scaffold exhibit interesting pharma‐ cological properties [6‐10]. Furthermore, pyridine is one of the most popular N‐heteroaromatics incorporated into the struc‐ ture of many pharmaceuticals. Among these, cyanopyridines with different alkyl and aryl groups were found to have antihypertensive [11], anti‐inflammatory, analgesic, anti‐ pyretic properties [12,13] as well as 1KK‐b inhibitor pro‐ perties [14]. Reactive oxygen species (ROS), including free radicals, led to a decrease in the antioxidant capacity and may generate other reactive species that damage the living cell. Oxidative stress may arise in a biological system after increasing exposure to oxidants, so the antioxidants play a major role in the protection of biological systems against threats. Different types of antioxidants such as Vitamins C and E, glutathione, lipoic acid and butylated phenols were widely used in different fields of industry and medicine to interrupt radical‐chain oxidation processes that attract a high scientific interest [15‐ 17]. We reported herein, the one pot multicomponent coupling synthesis of some 2‐aminopyridines in order to evaluate their antioxidant activities. 2. Experimental 2.1. Instrumentation All melting points are determined on Gallenkamp electric melting point apparatus (uncorrected). Thin layer chroma‐ tography (TLC) analysis was carried out on silica gel 60F254 precoated aluminum sheets. The IR spectra were recorded (KBr) on a on a Nicolet i55 FT‐IR Spectrophotometer at the Microanalytical Unit, Faculty of Science and Arts, Ulla, Taibah University, Kingdom of Saudi Arabia. 1H and 13C NMR spectra were recorded at 600 and 150 MHz, respectively, on a JEOL Spectrophotometer using CDCl3/DMSO‐d6 as solvent and TMS Gouda and Helal / European Journal of Chemistry 6 (1) (2015) 84‐87 85 a, R = H; b, R = CH3; c, R = OCH3; d, R = 4-Cl; e, X = O; f, X= S Scheme 1 as an internal reference, King Abdulaziz University, Faculty of Science, Kingdom of Saudi Arabia. The mass spectra (EI) were recorded on JEOL‐JMS 600 at Assiut University, Assiut, Egypt. Elemental analyses (C, H and N) were carried out at the Micro analytical Center, Cairo University, Giza, Egypt. Biological activities were carried at Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. 2.2. Synthesis 2.2.1. Synthesis of 2‐amino‐5‐isopropyl‐6‐methyl‐4‐aryl nicotinonitriles (4a‐f) General procedure: A mixture of aromatic aldehyde (20 mmol), 4‐methylpentan‐2‐one (1 g, 20 mmol), malononitrile (1.32 g, 20 mmol) and ammonium acetate (18.64 g, 160 mmol) in ethyl alcohol (30 mL) was heated under reflux for 24 h. The reaction mixture was cooled and the formed precipitate was filtered, washed with water, dried and crystallized from methanol to give compound 4a‐f (Scheme 1, Figure 1). 2‐Amino‐5‐isopropyl‐6‐methyl‐4‐phenylnicotinonitrile (4a): Color: White crystals. Yield: 73%. M.p.: 178‐179 °C. FT‐IR (KBr, ν, cm‐1): 3426, 3316 (NH2), 2208 (CN), 1650 (C=N). 1H NMR (600 MHz, DMSO‐d6, δ, ppm): 0.94 (d, 6H, J = 6.6 Hz, 2CH3), 2.10 (s, 1H, J = 6.6 Hz, CH), 2.52 (s, 3H, CH3), 5.88 (br, 2H, NH2), 7.48‐7.57 (m, 5H, Ar‐H). 13C NMR (150 MHz, DMSO‐d6, δ, ppm): 165.3 (C6), 160.5 (C2), 153.3 (C4), 136.9 (C1'), 129.4 (C4'), 128.6 (2C, C3', C5'), 128.1 (2C, C2', C6'), 117.3 (C5), 113.4 (CN), 86.4 (C3), 47.5 (C7), 28.6 (C8), 22.4 (2C, C9, C10). MS (EI, m/z (%)): 251.39 (M+, 9.2), 236 (41.8), 210 (27.5), 209 (100), 164 (11.3), 89 (17.6), 77 (63.3), 51 (15.6). Anal. calcd. for C16H17N3: C, 76.46; H, 6.82; N, 16.72. Found: C, 76.40; H, 6.85; N, 16.67%. 2‐Amino‐5‐isopropyl‐6‐methyl‐4‐p‐tolylnicotinonitrile (4b): Color: Yellow crystals. Yield: 74%. M.p.: 194‐196 °C. FT‐IR (KBr, ν, cm‐1): 3411, 3320 (NH2), 2211 (CN), 1651 (C=N). 1H NMR (600 MHz, CDCl3, δ, ppm): 0.95 (d, 6H, J = 6.6 Hz, 2CH3), 2.09 (septet, 1H, J = 6.6 Hz, CH), 2.42 (s, 3H, CH3Ar) 2.53(s, 3H, CH3), 5.32 (br, 2H, NH2), 7.30 (dd, 2H, J = 7.2 Hz, Ar‐H) 7.48 (dd, 2H, J = 7.2 Hz, Ar‐H). 13C NMR (150 MHz, CDCl3, δ, ppm): 165.4 (C6), 160.2 (C2), 154.2 (C4), 139.9 (C4'), 133.9 (C1'), 129.5 (2C, C3', C5'), 128.1 (2C, C2', C6'), 117.3 (C5), 114.1 (CN), 87.1 (C3), 47.8 (C7), 28.8 (C8), 22.5 (2C, C9, C10), 21.4 (CH3Ar). MS (EI, m/z (%)): 264.3 (M+ ‐1, 0.1), 250 (10.8), 223 (100), 210 (2.5), 193 (4.2), 166 (5.2), 140 (16.0), 115 (30.7), 91 (28.8), 77 (13.9), 65 (32.4), 51 (24.9). Anal. calcd. for C17H19N3: C, 76.95; H, 7.22; N, 15.84. Found: C, 76.91; H, 7.18; N, 15.78%. 2‐Amino‐5‐isopropyl‐4‐(4‐methoxyphenyl)‐6‐methylnicotino nitrile (4c): Color: Pale yellow crystals. Yield: 80%. M.p.: 171‐ 173 °C. FT‐IR (KBr, ν, cm‐1): 3405, 3315 (NH2), 2212 (CN), 1648 (C=N). 1H NMR (600 MHz, CDCl3, δ, ppm): 0.95 (d, 6H, J = 6.6 Hz, 2CH3), 2.09 (septet, 1H, J = 6.6 Hz, CH), 2.51 (s, 3H, CH3), 3.87 (s, 3H, OCH3Ar), 5. 28 (br, 2H, NH2), 7.01 (dd 2H, J = 9.0 Hz, Ar‐H), 7.55 (dd 2H, J = 9.0 Hz, Ar‐H). 13C NMR (150 MHz, CDCl3, δ, ppm): 163.3 (C6), 160.8 (C4'), 160.2 (C2), 153.8 (C4), 129.6 (2C, C2', C6'), 129.0 (C1') 117.6 (C5), 114.3 (2C, C3', C5'), 113.9 (CN), 86.9 (C3), 55.4 (OCH3Ar), 47.8 (C7), 28.8 (C8), 22.5 (2C, C9, C10) 163.3 (C6), 160.8 (C4'), 160.2 (C2), 153.8(C4), 129.6 (2C, C2', C6'), 129.0 (C1') 117.6 (C5), 114.3 (2C, C3', C5'), 113.9 (CN), 86.9 (C3), 55.4 (OCH3Ar), 47.8 (C7), 28.8 (C8), 22.5 (2C, C9, C10). MS (EI, m/z (%)): 263 (M+ ‐NH3, 11.7), 240 (20.1), 239 (100), 224 (9.5), 196 (10.1), 142 (10.9), 114 (22.9), 103 (17.2), 77 (23.6), 63 (41.3), 51 (32.4). Anal. calcd. for C17H19N3O: C, 72.57; H, 6.81; N, 14.94. Found: C, 72.51; H, 6.85; N, 14.90%. 2‐Amino‐5‐isopropyl‐4‐(4‐chlorophenyl)‐6‐methylnicotino nitrile (4d): Color: Pale yellow crystals. Yield: 70%. M.p.: 210‐ 212 °C. FT‐IR (KBr, ν, cm‐1): 3416, 3316 (NH2), 2212 (CN), 1650 (C=N). 1H NMR (600 MHz, DMSO‐d6, δ, ppm): 0.94 (d, 6H, J = 6.6 Hz, 2CH3), 2.10 (septet, 1H, J = 6.6 Hz, CH), 2.51(s, 3H, CH3), 6.17 (br, 2H, NH2), 7.48 (dd, 2H, J = 8.4 Hz, Ar‐H), 7.53 (dd, 2H, J = 8.4 Hz, Ar‐H). 13C NMR (150 MHz, DMSO‐d6, δ, ppm): 165.4 (C6), 160.7 (C2), 152.5 (C4), 135.5 (C1'), 135.1 (C4'), 129.6 (2C, C3', C5') 128.7 (2C, C2', C6'), 117.0 (C5), 112.8 (CN), 85.9 (C3), 47.4 (C7), 28.5 (C8), 22.4 (2C, C9, C10). MS (EI, m/z (%)): 270 (M+‐CH3, 11.7), 265 (11.7), 245 (31.9), 243 (100), 191 (10.65), 196 (10.1), 164 (11.1), 140 (7.7), 127 (7.7), 113 (8.8), 77 (10.9), 63 (26.4), 51 (41.4). Anal. calcd. for C16H16 ClN3: C, 67.25; H, 5.64; N, 14.70. Found: C, 67.32; H, 5.70; N, 14.65 %. 86 Gouda and Helal / European Journal of Chemistry 6 (1) (2015) 84‐87 Figure 1. The possible mechanism for synthesis of 2‐aminopyridines. 2‐Amino‐4‐(furan‐2‐yl)‐5‐isopropyl‐6‐methylnicotinonitrile (4e): Color: Grey crystals. Yield: 63%. M.p.: 196‐198 °C. FT‐IR (KBr, ν, cm‐1): 3425, 3319 (NH2), 2207 (CN), 1645 (C=N). 1H NMR (600 MHz, DMSO‐d6, δ, ppm): 0.94 (d, 6H, J = 6.6 Hz, 2CH3), 2.10 (septet, 1H, J = 6.6 Hz, CH), 2.51 (s, 3H, CH3), 5.73 (br, 2H, NH2), 6.59 (dd, 1H, J = 1.8 and 3.6 Hz, H4‐furan), 7.40 (d, 1H, J = 3.6 Hz, H3‐furan), 7.62(d, 1H, J = 3.3 Hz, H5‐furan). 13C NMR (150 MHz, DMSO‐d6, δ, ppm): 165.6 (C6), 160.6 (C2), 148.7 (C4), 144.2 (C2'), 140.6 (C5'), 117.7 (C5), 112.7 (CN), 112.4 (C3'), 108.6 (C4'), 81.4 (C4), 47.7 (C7), 28.6 (C8), 22.4 (2C, C9, C10). MS (EI, m/z (%)): 241 (M+, 13.1), 226 (16.4), 200 (19.0), 199 (100), 185 (4.4), 129 (10.0), 127 (12.9), 103 (10.7), 91 (12.8), 77 (16.4), 63 (26.5), 51 (24.3). Anal. calcd. for C14H15N3O: C, 69.69; H, 6.27; N, 17.14. Found: C, 69.63; H, 6.21; N, 17.10%. 2‐Amino‐5‐isopropyl‐6‐methyl‐4‐(thiophen‐2‐yl)nicotine nitrile (4f): Color: Yellowish white crystals. Yield: 61%. M.p.: 185‐187 °C. FT‐IR (KBr, ν, cm‐1): 3423, 3319 (NH2), 2202 (CN), 1645 (C=N). 1H NMR (600 MHz, DMSO‐d6, δ, ppm): 0.94 (d, 6H, J = 6.6 Hz, 2CH3), 2.09 (septet, 1H, J = 6.6 Hz, CH), 2.48 (s, 3H, CH3), 6.09 (br, 2H, NH2), 7.18 (dd , 1H, J = 1.2 and 4.2 Hz, H4‐ thiophene), 7.55 (dd, 1H, J = 1.2 and 3.6 Hz, H5‐thiophene), 7.77 (dd, 1H, J = 1.2 and 3.6 Hz, H3‐thiophene). 13C NMR (150 MHz, DMSO‐d6, δ, ppm): 165.6 (C6), 160.6 (C2), 148.7 (C4), 144.2 (C2'), 140.6 (C5'), 117.7 (C5), 112.7 (CN), 112.4 (C3'), 108.6 (C4'), 81.4 (C4), 47.7 (C7), 28.6 (C8), 22.4 (2C, C9, C10). MS (EI, m/z (%)): 259 (M++2, 0.3), 257 (M+, 33.8), 242 (12.7), 215 (100) 200 (14.6), 197 (18.6), 185 (12.3), 174 (20.7), 157 (17.3), 108 (14.2), 91 (11.6), 77 (11.8), 63 (17.5). Anal. calcd. for C14H15N3S: C, 65.34; H, 5.87; N, 16.33. Found: C, 65.28; H, 5.82; N, 16.27%. 2.2.2. ABTS Antioxidant assay [18] Antioxidant activity determinations were evaluated from the bleaching of ABTS derived radical cations. The radical cation was derived from ABTS [2,2'‐azino‐bis (3‐ethyl benzo thiazoline‐6‐sulfonic acid)] was prepared by reaction of ABTS (60 μL) with MnO2 (3 mL, 25 mg/mL) in 5 mL aqueous buffer solution (pH = 7). After shaking the solution for a few minutes, it was centrifuged and filtered. The absorbance (A control) of the resulting green‐blue solution (ABTS radical solution) was recorded at λmax = 734 nm. The absorbance (A test) was measured upon the addition of (20 μL of 1 mg/mL) solution of the tested sample in spectroscopic grade MeOH:Buffer (1:1, v:v) to the ABTS solution. The decrease in the absorbance is expressed as %inhibition which calculated from the Equation (1). % Inhibition= [A (control) ‐ A (test)/ A (control)] × 100 (1) Ascorbic acid (20 μL, 2 mM) solution was used as standard antioxidant (positive control). Blank sample was run using solvent without ABTS (Table 1). Table 1. ABTS Antioxidant activity assay of the new compounds. Compound no Absorbance of samples (λ, 734 nm) % Inhibition 4a 0.416 16.8 4b 0.489 2.2 4c 0.420 16.0  4d 0.428 14.4 4e 0.407 18.6 4f 0.320 36.0 Control of ABTS a 0.500 0.0 Ascorbic acid 0.061 87.8 a ABTS: The method used for antioxidant activity, (%) Inhibition = [A (control) – A (test) /A (control)] × 100. 3. Results and discussion 3.1. Chemistry Scheme 1 describes the synthesis of the target molecules. The target compounds 2‐amino‐5‐isopropyl‐4‐(4‐aryl)‐6‐ methylnicotinonitrile (4a‐f) were obtained with high yield and purity via one‐pot condensation of malononitrile (1), 4‐ methylpentan‐2‐one (2), aryl carboxaldehyde (3a‐f) and ammonium acetate in ethanol. The structure of compounds 4a‐f was established by the spectral data. Whereas, the IR spectra showed characteristic absorption bands within 3426‐3315 cm‐1, corresponding to amino groups, 2212‐2202 cm‐1 due to cyano groups and 1651‐ 1648 cm‐1 corresponding to C=N groups. Further, their 1H NMR displayed singlet signal within δ 2.52‐2.48 ppm, which Gouda and Helal / European Journal of Chemistry 6 (1) (2015) 84‐87 87 corresponding to three proton of CH3, doublet signal within δ 2.10‐2.09 ppm, which due to two C9,10H3 groups, septets within δ 2.10‐2.09 ppm due to one proton of C7H groups and broad singlet signal corresponding to two protons of amino groups. The 1H NMR of compound 4b and 4c exhibited two singlet signals at 2.42 and 3.87 ppm corresponding to methyl and methoxy protons, respectively. Moreover the 13C NMR of compounds 4a‐f displayed signals within δ 165.6‐163.3, 160.7‐ 160.2, 153.8‐145.2, 117.7‐117.0 and 87.1‐81.4 ppm due to pyridine nucleus. Furthermore, the mass spectra of compounds 4a‐f displayed the base beaks at m/z 208, 222, 238, 242, 198 and 214, respectively due to M+‐isopropyl moiety. The formation of compounds 4a‐f can be explained in the following possible mechanism Figure 1. There are two routes in the first one: the ketone (2) reacted with ammonium acetate to form the enamine derivative II which reacted with the arylidene derivative III [which formed from reaction of aldehyde 3 and malononitrile (1)] to form the Micheal adducts IV, the intermediate IV cyclized to dihydropyridine V then autoxidized to aminopyridine 4a‐f, Figure 1. 3.2. ABTS Antioxidant assay The newly synthesized compounds were screened for their antioxidant activity using 2,2'‐azino‐bis‐(3‐ethylbenzothiazo line‐6‐sulfonic acid) (ABTS) method which reported by Lissi et al. [18]. The antioxidant activity assay employed here is one of the several assays that depends on measuring the consumption of stable free radicals i.e. evaluate the free radical scavenging activity of the investigated component. The methodology assumes that the consumption of the stable free radical (X') will be determined by reactions as followed: XH + Y' → X' + YH (2) Total antioxidant potential of resinous exudates from Heliotropium species, and a comparison of the ABTS methods. The rate and/or the extent of the process measured in terms of the decrease in X' concentration, would be related to the ability of the added compounds to trap free radicals. The decrease in color intensity of the free radical solution due to scavenging of the free radical by the antioxidant material is measured calorimetrically at a specific wavelength. The assay employs the radical cation derived from 2,2'‐azino‐bis‐(3‐ethyl benzthiazoline‐6‐sulfonic acid) as stable free radical to assess antioxidant potential of the investigated compounds [19,20]. The results showed that compounds 4a‐f displayed weak antioxidant activities. By comparing the results obtained of antioxidant of the compounds reported in this study to their structures, the following structure activity relationship (SARs) were postulated: i. Compound 4e is more potent than compound 4a which may be due to replacement of phenyl moiety by furan, ii. Compound 4e has activity less than compound 4f which may be attributed to replacement of furan moiety by thiophene, iii. Compounds 4b, 4c and 4d are less potent than compound 4a due to presence of electron donating group. 4. 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