Synthesis of new 6-substituent 2-phenyl and 2-(furan-2-yl)-3-phenyl-quinoline-4-carboxylic acid derivatives European Journal of Chemistry 10 (1) (2019) 57-63 European Journal of Chemistry View Journal Online View Article Online Synthesis of new 6-substituent 2-phenyl and 2-(furan-2-yl)-3-phenyl- quinoline-4-carboxylic acid derivatives Tawassl Tajelsir Hassan Hajalsiddig * and Ahmed Elsadig Mohammed Saeed Department of Chemistry, Collage of Science, Sudan University of Science and Technology, Khartoum, 407, Sudan toooota7@hotmail.com (T.T.H.H.), aemsaeed@gmail.com (A.E.M.S.) * Corresponding author at: Department of Chemistry, Collage of Science, Sudan University of Science and Technology, Khartoum, 407, Sudan. Tel: +249.183.769363 Fax: +249.183.774559 e-mail: toooota7@hotmail.com (T.T.H. Hajalsiddig). 10.5155/eurjchem.10.1.57-63.1816 Received: 20 November 2018 Received in revised form: 24 December 2018 Accepted: 26 December 2018 Published online: 31 March 2019 Printed: 31 March 2019 A synthesis of substituted quinolines has been achieved by the Doebner reaction which is a three component coupling of arylaldehyde, p-amino-acetophenone and phenyl pyruvic acid. The products of 2,3-diary-6-acetyl-quinoline-4-carboxylic acids were obtained by Claisen Schmidt condensation reaction with aldehydes in the presence of sodium hydroxide in order to give the corresponding α,β-unsaturated carbonyls. The substituted α,β-unsaturated carbonyls were condensed with urea, thiourea, hydrazine, phenyl hydrazine, semicarbazide hydrochloride and ethanolamine to synthesized 2-pyrimidinone, 2-pyrimidinethion, pyrazoline-1-phenyl, pyrazoline, pyrazoline-1-carboxamide and 1,4-oxazepines derivatives, respectively, with good yields. The purity and identities of products were elucidated through thin layer chromatography (TLC), melting point and spectroscopic data (IR, 1H NMR, 13C NMR and LC-Mass). Synthesis Quinoline Pyrazoline Heterocyclic Pyrimidinone α,β-Unsaturated carbonyl Cite this: Eur. J. Chem. 2019, 10(1), 57-63 Journal website: www.eurjchem.com 1. Introduction Quinoline also known as 1-azanapthaline, 1-benzazine or benzo[b]pyridine is a heterocyclic organic compounds, with formula C9H7N and it is a colorless liquid with strong odor. It was first extracted from coal tar in 1834 by Friedlieb Ferdinand Runge [1]. It can form salt with acids and displays reactions similar to those of pyridine and benzene. It shows both electrophilic and nucleophilic substitution reactions. It is nontoxic to humans on oral absorption and inhalation [2]. Quinoline is a pharmacologically valuable scaffold that is prevalent in a variety of biologically active synthetic and natural compounds [3], throughout the 20th century, the chemistry of quinolones has been the subject of intense study and different interesting bioactivity such as anticancer [4], antibacterial [5], antifungal [6], antitumor [7], anti-HIV-1 [8], antileishmanial [9] and antimalarial activity [10]. There are number of natural products of quinoline skeleton used as a medicine or employed as lead molecule for the development newer and potent molecules. For example, quinine was isolated as the active ingredient from the bark of Cinchona trees and has been used for the treatment of malaria [11]. The increased resistance of microbial to known quinolines is constantly demanding to generate novel quinolines to meet the requirements [12]. These quinolines have been of considerable interest because a large number of natural products and drugs contain this heterocyclic unit. Further, these compounds are used as building blocks of various other compounds such as α,β-unsaturated carbonyls, pyrazolines, cyanopyridines, isoxazoles, sulphonamides, arylamides, thiopyrimidines and amino pyrimidines etc. [13]. These compounds are known to possess biological activities [14]. In the present work, our interest towered the development of novel heterocycles. The synthesis of 6-substituent-2,3- diaryl-4-quinoline carboxylic acid (1,9) were reported. The resulting compounds were then condensed with arylaldehydes to product analogies α,β-unsaturated carbonyls which were cyclized with urea derivatives, hydrazine derivatives and monoethanolamine to form pyrimidinone/thiones, pyrazoline, and oxazepines rings. 2. Experimental 2.1. Instrumentation The 1H and 13C spectra were recorded on Ultrashield 500 plus instrument (Bruker, Germany) using CDCl3 as solvent and operating at 500 MHz for protons. Chemical shifts (δ) are ABSTRACT RESEARCH ARTICLE KEYWORDS European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2019 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. http://dx.doi.org/10.5155/eurjchem.10.1.57-63.1816 http://dx.doi.org/10.5155/eurjchem.10.1.57-63.1816 https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.10.1.57-63.1816&domain=pdf&date_stamp=2019-03-31 http://www.eurjchem.com/ http://dx.doi.org/10.5155/eurjchem.10.1.57-63.1816 mailto:toooota7@hotmail.com mailto:aemsaeed@gmail.com mailto:toooota7@hotmail.com http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.10.1.57-63.1816&domain=pdf&date_stamp=2019-03-31� 58 Hajalsiddig and Saeed / European Journal of Chemistry 10 (1) (2019) 57-63 given from TMS (0.00 ppm) as an internal standard for 1H NMR. Mass spectra analysis was carried out using a Bruker Daltonics Squire 4000 instrument. Melting points were determined on an automatic Electrothermal melting point apparatus and are uncorrected. The IR spectra were determined in potassium bromide pellets on an Agilent Cary 630 FT-IR system. 2.2. General method for synthesis 2, 3-diaryl-quinoline-4- carboxylic acid derivatives (1, 9) In round bottom flask equipped with a reflux condenser were placed 0.236 mol of the required aromatic aldehyde, 0.25 mol of freshly distilled phenyl pyruvic acid and 200 mL of absolute ethanol. The mixture was heated on a boiling water- bath and a solution of 0.248 mol of p-amino-acetophenone in a 100 mL of absolute ethanol was added slowly with frequent shaking within 1 hour. The mixture was refluxed on a water- bath for 3 hours and left to stand overnight, filtered, washed with little ether and recrystallized from ethanol to yield compounds 1 and 9 (Scheme 1). 6-Acetyl-2,3-diphenylquinoline-4-carboxylic acid (1): Color: Off white crystals. Yield: 2.91 g, 93%. M.p.: 210-212 °C. FT-IR (KBr, ν, cm-1): 3247 (O-H), 3090 (Ar-H), 1679 (C=O) (keto), 1668 (C=O) (acid), 1600 (C=C), 1362 (C-N). 1H NMR (500 MHz, CDCl3, δ, ppm): 2.65 (s, 3H, CH3), 7.16-7.45 (m, 6H, Ar-H), 7.67 (t, 2H, Ar-H), 7.98 (d, 2H, H-Ar), 8.22 (d, 1H, CH quinoline), 8.41 (d, 1H, CH quinoline), 9.45 (s , 1H, CH quinoline), 12.82 (s , 1H, COOH). 13C NMR (125 MHz, CDCl3 δ, ppm): 26.45 (CH3), 127.70 (Ar-C), 128.22 (Ar-C), 128.53 (Ar-C), 128.78 (Ar-C), 129.02 (Ar-C), 129.37 (Ar-C), 129.58 (CH-CH-CN), 133.46 (Ar- C-C), 135.78 (C-COOH), 166.50 (COOH), 189.12 (C=O). MS (EI, m/z (%)): 367.43 (M+, 2.3), 248.11 (M+-C8H3O, 40.5), 205.00 (M+-C9H4O3, 6.1), 124.05 (M+-C15H9O3, 100). 6-Acetyl-2-(furan-2-yl)-3-phenylquinoline-4-carboxylic acid (9): Color: Beige crystals. Yield: 2.40 g, 82%. M.p.: 143-145 °C. FT-IR (KBr, ν, cm-1): 3243 (OH), 3144 (Ar-H), 1675 (C=O) (keto), 1667 (C=O) (acid), 1599 (C=C), 1362 (C-N). 1H NMR (500 MHz, CDCl3, δ, ppm): 2.65 (s, 3H, CH3), 6.32 (t, 1H, H- furyl), 7.30 (t, 1H, H-Ar), 7.35 (t, 2H, H-Ar), 7.70 (d, 2H, H-Ar), 7.75 (d, 1H, H-furyl), 7.95 (d, 1H, H-furyl), 8.22 (d, 1H, CH quinoline), 8.42 (d, 1H, CH quinoline), 9.66 (s, 1H, CH quinoline), 10.68 (s, 1H, COOH). 13C NMR (125 MHz, CDCl3 δ, ppm): 26.49 (1C. CH3), 110.19 (1C, CH=CH-O), 127.31 (1C, Ar- C), 128.33 (2C, Ar-C), 129.43 (2C, Ar-C), 133.53 (1C, Ar-C-C), 142.91 (1C, CH-O-C), 148.52 (1C, C-N=C), 166.17 (1C, COOH), 196.07 (1C, C=O). MS (EI, m/z (%)): 357.34 (M+, 17.8), 318.29 (M+- C2H3O, 32.14), 293.06 (M+- C4H3O, 7.9) 248.11(M+-C6H6O2, 100). 2.3. General method for synthesis α,β-unsaturated carbonyl derivatives (2 and 10) A mixture of 0.01 mol of the required aromatic aldehyde and 0.01 mol of substituted quinoline was stirred in 30 mL of ethanol at room temperature in the presence of 10 mL of 20% sodium hydroxide solution. The mixture was stirred for 24 hours at room temperature and kept for overnight at room temperature. The mixture was poured into crushed ice and acidified with dilute hydrochloric acid. The α,β-unsaturated carbonyl derivatives were precipitated out as solid, filtered, dried and recrystallized from ethanol to yield compounds (2 and 10) (Scheme 1). 6-Cinnamoyl-2,3-diphenylquinoline-4-carboxylic acid (2): Color: Pale yellow crystals. Yield: 1.22 g, 86%. M.p.: 110-112 °C. FT-IR (KBr, ν, cm-1): 3285 (OH), 3060 (C-H) (=CHα), 3045 (C-H) (=CHπ), 1682 (C=O) (keto), 1657 (C=O) (acid), 1598 (C=C), 1356 (C-N). 1H NMR (500 MHz, CDCl3, δ, ppm): 7.22- 7.74 (m, 12H, H-Ar, Hα-C=), 7.58-7.76 (m, 3H, H-Ar, Hβ-C= ), 7.93 (d, 2H, H-Ar), 8.13 (d, 1H, CH quinoline), 8.51 (d, 1H, CH quinoline), 9.72 (s, 1H, CH quinoline), 12.11 (s, 1H, COOH). 13C NMR (125 MHz, CDCl3 δ, ppm): 121.69 (1C, -Cα=), 127.81 (1C, CH-CH-CN), 127.66 (2C, Ar-C), 128.24 (1C, Ar-C), 128.48 (2C, Ar-C), 128.69 (1C, Ar-C), 129.00 (2C, Ar-C), 129.35 (2C, Ar-C), 129.53 (1C, CH-CH-CN), 133.46 (1C, Ar-C-C), 134.84 (1C, -Cβ=), 135.90 (1C, C-COOH), 141.56 (1C, Ar), 189.14 (1C, C=O), 166.76 (1C, COOH). MS (EI, m/z (%)): 455.52 (M+, 4.8), 437.18 (M+-18, 100), 303.25 (M+-C12H10, 7.5). 2-(Furan-2-yl)-6-(3-(furan-2-yl) acryloyl)-3-phenyl quinoli ne-4-carboxylic acid (10): Color: Beige crystals. Yield: 1.56 g, 78%. M.p.: 148-150 °C. FT-IR (KBr, ν, cm-1): 3275 (OH), 3060 (C-H) (=CHα), 3045 (C-H) (=CHπ), 1672 (C=O) (keto), 1660 (C=O) (acid), 1600 (C=C), 1365 (C-N). 1H NMR (500 MHz, CDCl3, δ, ppm): 6.16-6.32 (m, 2H, 2H-furyl), 7.23 (t, 1H, H-Ar), 7.36 (t, 2H, H-Ar), 7.70 (d, 2H, H-Ar), 7.73-7.78 (m, 2H, H-furyl, Hα-C= ), 7.95 (d, 1H, H-furyl), 7.99-8.10 (m, 3H, 2H-furyl, Hβ- C=), 8.12 (d, 1H, CH quinoline), 8.19 (d, 1H, CH quinoline), 9.66 (s, 1H, CH quinoline), 10.62 (s, 1H, COOH). 13C NMR (125 MHz, CDCl3 δ, ppm): 110.18 (1C, CH=CH-O), 119.99 (1C, -Cβ=), 127.31 (1C, Ar-C), 128.62 (2C, Ar-C), 129.43 (2C, Ar-C), 131.25 (1C, -Cα=), 133.55 (1C, Ar-C-C), 140.76 (1C, CH-O-C), 142.90 (1C, CH-O-C), 148.54 (1C, C-N=C), 166.21 (1C, COOH), 196.08 (1C, C=O). MS (EI, m/z (%)): 435.44 (M+, 1.1), 382.06(M+- C3H2O, 100), 360.11 (M+- C6H5, 58.1), 360.11 (M+- C11H8O2, 77.4), 2.4. General method for synthesis 2-pyrimidinone/thiones derivatives (3, 4, 11 and 12) A mixture of 0.01 mol of α,β-unsaturated carbonyl (2 or 10), 0.01 mol of urea or thiourea dissolved in 50 mL of ethanol and 6 mL of aqueous sodium hydroxide (10%) was added. The reaction of mixture was heated under reflux for 3 h. TLC monitoring was extensively done. The product when cool was poured in ice-cold water. The solid mass which separated out was filtered washed with water and recrystallized from ethanol to yield compounds 3, 4, 11 and 12 (Scheme 2). 6-(2-Oxo-6-phenyl-1, 2-dihydropyrimidin-4-yl)-2,3-diphenyl quinoline-4-carboxylic acid (3): Color: Yellow crystals. Yield: 0.42 g, 70%. M.p.: 175-177 °C. FT-IR (KBr, ν, cm-1): 3226 (OH), 3090 (CH), 3015 (NH), 1692 (C=O) (acid), 1672 (C=O) (amide), 1601 (C=C), 1376 (C-N). 1H NMR (500 MHz, CDCl3, δ, ppm): 5.73 (s, 1H, CH), 7.14-7.38 (m, 8H, H-Ar), 7.46 (d, 2H, H-Ar), 7.62-7.67 (m, 3H, H-Ar) 7.85 (d, 2H, H-Ar), 8.02 (d, 1H, CH quinoline ring), 8.85 (d, 1H, CH quinoline), 9.83 (s, 1H, CH quinoline), 10.02 (s, 1H, NH), 12.32 (s, 1H, COOH). 13C NMR (125 MHz, CDCl3 δ, ppm): 101.05 (1C, CH-CNH), 122.03 (1C, C- CCOOH), 127.46 (1C, Ar-C), 127.70 (2C, Ar-C), 127.80 (2C, Ar- C), 128.08 (1C, Ar-C), 128.41 (2C, Ar-C), 128.45 (2C, Ar-C), 128.70 (1C,Ar-C), 128.97 (2C, Ar-C), 129.04 (2C, Ar-C), 129.34 (1C, CH-CH-CN), 133.05 (1C, Ar-C-C), 133.36 (1C, C-COOH), 141.25 (1C, Ar), 157.12 (1C, C=O), 166.94 (1C, COOH). MS (EI, m/z (%)): 497.54, ([M++2], 56.1), 496.16 ([M++1], 5.4), 495.18 (M+, 3.2), 248.11 (M+- C16H12N2O, 100). 2,3-Diphenyl-6-(6-phenyl-2-thioxo-1,2-dihydropyrimidin-4- yl)quinoline-4-carboxylic acid (4): Color: Yellow crystals. Yield: 0.41 g, 68%. M.p.: 165-167 °C. FT-IR (KBr, ν, cm-1): 3209 (OH), 3210 (NH), 1692 (C=O) (acid), 1672 (C=O) (amide), 1600 (C=N), 1426 (C=C), 1210 (C=S), 1365 (C-N). 1H NMR (500 MHz, CDCl3, δ, ppm): 5.96 (s, 1H, CH), 7.13-7.34 (m, 8H, H-Ar), 7.39 (d, 2H, H-Ar), 7.61-7.68 (m, 3H, H-Ar), 7.84 (d, 2H, H-Ar), 8.02 (d, 1H, CH quinoline ), 9.02 (d, 1H, CH quinoline), 9.24 (s, 1H, CH quinoline), 10.02 (s, 1H, NH), 12.43 (s, 1H, COOH). 13C NMR (125 MHz, CDCl3 δ, ppm): 101.05 (1C, CH-CNH), 121.91 (1C, C- CCOOH), 127.30 (1C, Ar-C), 127.67 (2C, Ar-C), 127.81 (2C, Ar- C), 128.13 (1C, Ar-C), 128.37 (2C, Ar-C), 128.48 (2C, Ar-C), 128.70 (1C,Ar-C), 128.88 (2C, Ar-C), 129.14 (2C, Ar-C), 129.34 (1C, CH-CH-CN), 130.93 (1C, Ar-C-C), 133.44 (1C, C-COOH), 141.80 (1C, Ar), 174.97 (C, C-NH), 166.76 (1C, COOH). 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.1.57-63.1816 Hajalsiddig and Saeed / European Journal of Chemistry 10 (1) (2019) 57-63 59 N COOHO R R1 (2,10) N COOHO 20% NaOHeq NH2 + N COOHO R (1,9) Reflux/ethanol 24 h / 25 oC O Compound 2, R and R1= N COOHO O O O O (1) (9) O Compound 10, R and R1= Compound 1, R = Compound 9, R = (a) (b) (c) O COOH O H3C Reflux/ethanol (c) R1 O H Scheme 1. Synthesis of 2,3-diaryl -quinoline-4-carboxylic acid and α,β-unsaturated carbonyl analogues. MS (EI, m/z (%)): 513.60 ([M++2], 4.2), 512.18 ([M++1], 8.7), 511.27(M+, 10.8), 437. 17 (M+-CHN2S). 2-(Furan-2-yl)-6-(6-(furan-2-yl)-2-oxo-1, 2-dihydropyrimi din-4-yl)-3-phenylquinoline-4-carboxylic acid (11): Color: Brown crystals. Yield: 0.43 g, 72%. M.p.: 147-149 °C. FT-IR (KBr, ν, cm-1): 3293 (OH), 3196 (NH), 3089 (CH), 1692 (C=O) (acid), 1673, 1672 (C=O) (amide), 1600 (C=C), 1376 (C-N). 1H NMR (500 MHz, CDCl3, δ, ppm): 6.04 (s, 1H, CH), 6.17-6.33 (m, 2H, H-furyl),7.22- 7.36 (m, 3H, H-Ar), 7.68-7.80 (m, 5H, H-furyl , H-Ar), 7.96 (d, 1H, H-furyl), 8.10 (d, 1H, CH quinoline), 8.12 (d, 1H, CH quinoline), 9.67 (s, 1H, CH quinoline), 10.02 (s, 1H, NH), 11.01 (s, 1H, COOH). 13C NMR (125 MHz, CDCl3 δ, ppm): 110.18 (1C, CH=C-O), 110.84 (1C, CH=C-O), 112.44 (1C, CH- CNH), 128.32 (2C, Ar-C), 127.31 (1C, Ar-C), 128.62 (2C, Ar-C), 129.43 (2C, Ar-C), 133.55 (1C, Ar-C-C), 140.76 (1C, CH-O-C), 141.69 (1C, C-NH), 142.90 (1C, CH-O-C), 148.54 (1C, C-N=C), 156.28 (1C, C=O), 166.29 (1C, COOH). MS (EI, m/z (%)): 477.41 ([M++2], 2.2), 476.13 ([M++1], 1.3), 475.08(M+, 1.7), 382.09 (M+- C6H7O, 100). 2-(Furan-2-yl)-6-(6-(furan-2-yl)-2-thioxo-1,2-dihydropyrimi din-4-yl)-3-phenylquinoline-4-carboxylic acid (12): Color: Brown crystals. Yield: 0.40 g, 67%. M.p.: 150-152 °C. FT-IR (KBr, ν, cm-1): 3289 (OH), 3190 (NH), 1675 (C=O) (acid), 1600 (C=N), 1503 (C=N), 1226 (C=S), 1366 (C-N). 1H NMR (500 MHz, CDCl3, δ, ppm): 6.04 (s, 1H, CH), 6.17-6.31 (m, 2H, H- furyl), 7.24- 7.36 (m, 3H, H-Ar), 7.69-7.78 (m, 5H, H-furyl , H- Ar), 7.95 (d, 1H, H-furyl), 8.10 (d, 1H, CH quinoline), 8.12 (d, 1H, CH quinoline), 9.67 (s, 1H, CH quinoline), 10.02 (s, 1H, NH), 10.89 (s, 1H, COOH). 13C NMR (125 MHz, CDCl3 δ, ppm): 110.19 (1C, CH=C-O), 110.84 (1C, CH=C-O), 112.43 (1C, CH-CNH), 127.31 (1C, Ar-C), 128.61 (2C, Ar-C), 129.43 (2C, Ar-C), 133.55 (1C, Ar-C-C), 140.76 (1C, CH-O-C), 141.73 (1C, C-NH), 142.90 (1C, CH-O-C), 148.55 (1C, C-N=C), 166.32 (1C, COOH). MS (EI, m/z (%)): 493.61, ([M++2], 2.5), 492.17 ([M++1], 4.9), 491.12 (M+, 5.1), 382.09 (M+- C6H5S, 100). 2.5. General method for synthesis pyrazoline/pyrazoline-1- phenyl/pyrazoline-1-carboxamide derivatives (5, 6, 7, 13, 14 and 15) A mixture of 0.01 mol of α,β-unsaturated carbonyl (2 or 10), 0.01 mol of hydrazine hydrochloride, phenyl hydrazine hydrochloride or pyrazoline-1-carboxamide dissolved in 25 mL of ethanol and 1 mL of ethanolic sodium hydroxide (0.1 mol) was added. The reaction mixture was heated under reflux for 2 h. TLC monitoring was extensively done. The product when cool was poured in ice-cold water. The solid mass which separated out was filtered washed with water and recrystallized from ethanol to yield compounds 5, 6, 7, 13, 14 and 15 (Scheme 2). 6-(1,5-Diphenyl-4,5-dihydro-1H-pyrazol-3-yl)-2,3-diphenyl quinoline-4-carboxylic acid (5): Color: Yellow crystals. Yield: 0.42 g, 70%. M.p.: 119-121 °C. FT-IR (KBr, ν, cm-1): 2956 (CH2), 1698 (C=O) (acid), 1601 (C=C), 1513 (C=N). 1H NMR (500 MHz, CDCl3, δ, ppm): 3.71-3.75 (dd, 1H(A), CH2, dd, 1H(B), CH2 ), 4.99-5.02 (dd, 1H(X),-CH), 6.61-6.63 (m, 3H, H-Ar), 7.11-7.44 (m, 11H, H-Ar), 7.63-7.90 (m, 4H, H-Ar), 8.09 (d, 2H, H-Ar), 8.22 (d, 1H, CH quinoline), 8.43 (d, 1H, CH quinoline), 9.61 (s, 1H, CH quinoline), 12.32 (s, 1H, COOH). 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.1.57-63.1816 60 Hajalsiddig and Saeed / European Journal of Chemistry 10 (1) (2019) 57-63 N COOHO R R1 R and R1= R1 R ON NHCOOH N (3, 11) NH2CONH2 R1 R N O COOH N NH2CSNH2 (4, 12) R1 R O NH2 N N COOH N R (5, 13) NH2NHPh.Cl R1 R N NH COOH N R1 NaOH, Alcohol N N COOH N NaOH, Alcohol R1 R SN NHCOOH N NaOH, Alcohol (6, 16) (7, 15) (8, 16) (2, 10) O Compounds 1-8 Compounds 9-16 R and R1= NaOH, Alcohol NH2NH2.Cl NH2NHCONH2 NH2CH2CH2OH NaOH NaOH Scheme 2. Synthesis of pyrimidinone/thiones, pyrazolines, and oxazepines substituent 2,3-diaryl-quinoline-4-carboxylic acids from α,β-unsaturated carbonyls. 13C NMR (125 MHz, CDCl3 δ, ppm): 41.25 (1C, CH2-CH), 63.31 (1C, C-N-N), 127.09 (2C, Ar-C), 127.69 (2C, Ar-C), 127.80 (2C, Ar-C), 128.08 (1C, Ar-C), 128.25 (2C, Ar-C), 128.55 (2C, Ar-C), 128.79 (1C,Ar-C), 128.95 (2C, Ar-C), 129.03 (2C, Ar-C), 129.38 (1C, CH-CH-CN), 133.05 (1C, Ar-C-C), 133.36 (1C, C- COOH), 141.12 (1C, Ar), 157.12 (1C, C=O), 166.38 (1C, COOH). MS (EI, m/z (%)): 547.17 ([M++2], 1.4), 546.15 ([M++1], 2.1), 545.15 (M+, 5.7), 363.21 (M+-C12H10N2, 100). 2, 3-Diphenyl-6-(5-phenyl-4, 5-dihydro-1H-pyrazol-3-yl) quinoline-4-carboxylic acid (6): Color: Pale yellow crystals. Yield: 0.39 g, 65%. M.p.: 128-131 °C. FT-IR (KBr, ν, cm-1): 3047 (NH), 2958 (C-H) (CH2), 1679 (C=O) (acid), 1602 (C=C), 1520 (C=N). 1H NMR (500 MHz, CDCl3, δ, ppm): 3.70-3.74 (dd, 1H(A), CH2, dd, 1H(B), CH2 ), 4.93-4.95 (dd, 1H(X),-CH), 7.19-7.33 (m, 5H, H-Ar), 7.50-7.69 (m, 6H, H-Ar), 7.93 (d, 2H, H-Ar), 8.02 (d, 2H, H-Ar), 8.31 (d, 1H, CH quinoline), 8.58 (d, 1H, CH quinoline), 9.88 (s, 1H, CH quinoline), 10.03 (s, 1H, NH), 12.46 (s, 1H, COOH). 13C NMR (125 MHz, CDCl3 δ, ppm): 41.27 (1C, CH2-CH), 63.31 (1C, C-N-N), 127.59 (2C, Ar-C), 127.69 (1C, Ar- C), 127.90 (2C, Ar-C), 128.10 (1C, Ar-C), 128.53 (2C, Ar-C), 128.77 (1C, Ar-C), 128.92 (2C, Ar-C), 128.97 (2C, Ar-C), 129.37 (1C, CH-CH-CN), 133.05 (1C, Ar-C-C), 133.36 (1C, C-COOH), 141.69 (1C, Ar), 151.36 (1C, C=N), 166.17 (1C, COOH). MS (EI, m/z (%)): 471.18 ([M++2], 64.7), 470.13 ([M++1], 17.6), 469.15 ([M+, 11.4), 274.24 (M+-C13H12N2, 100). 6-(1-Carbamoyl-5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-2,3 - diphenylquinoline-4-carboxylic acid (7): Color: Pale yellow crystals. Yield: 0.40 g, 67%. M.p.: 120-123 °C. FT-IR (KBr, ν, cm-1): 3326 (OH), 3101 (NH), 2952 (C-H) (CH2), 1706 (C=O) (acid), 1681 (C=O) (amide), 1600 (C=C), 1516 (C=N). 1H NMR 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.1.57-63.1816 Hajalsiddig and Saeed / European Journal of Chemistry 10 (1) (2019) 57-63 61 (500 MHz, CDCl3, δ, ppm): 3.70-7.74 (dd, 1H(A), CH2, dd, 1H(B), CH2 ), 4.93-4.98 (dd, 1H(X), -CH), 6.01 (s, 2H, NH2), 7.16-7.50 (m, 5H, H-Ar), 7.77-7.60 (m, 6H, H-Ar), 8.02-7.94 (m, 4H, H- Ar), 8.22 (d, 1H, CH quinoline), 8.47 (d, 1H, CH quinoline), 9.50 (s, 1H, CH quinoline), 12.30 (s, 1H, COOH). 13C NMR (125 MHz, CDCl3 δ, ppm): 41.27 (1C, CH2-CH), 63.29 (1C, C-N-N), 127.40 (1C, Ar-C), 127.67 (2C, Ar-C), 127.82 (2C, Ar-C), 128.07 (1C, Ar-C), 128.46 (2C, Ar-C), 128.62 (1C,Ar-C), 128.85 (2C, Ar-C), 129.10 (2C, Ar-C), 129.52 (1C, CH-CH-CN), 133.71 (1C, C- COOH), 142.03 (1C, Ar), 150.16 (1C, C=N), 156.87 (1C, NH2- C=O), 166.71 (1C, COOH). MS (EI, m/z (%)): 514.16 ([M++2], 11.9), 513.16 ([M++1], 13.9), 512.44 (M+, 34.5), 274.24 (M+- C15H14N2O, 100). 2-(Furan-2-yl)-6-(5-(furan-2-yl)-1-phenyl-4, 5-dihydro-1H- pyrazol-3-yl)-3-phenylquinoline-4-carboxylic acid (13): Color: Pale yellow crystals. Yield: 0.39 g, 65%. M.p.: 145-150 °C. FT-IR (KBr, ν, cm-1): 3276 (OH), 2805 (C-H) (CH2), 1671 (C=O) (acid), 1598 (C=C), 1510 (C=N), 1269 (C-O). 1H NMR (500 MHz, CDCl3, δ, ppm): 3.63-3.68 (dd, 1H(A), CH2, dd, 1H(B), CH2), 4.09-4.14 (dd, 1H(X), -CH), 6.62 (d , 1H, H-furyl), 6.17-6.29 (m, 3H, H- furyl, H-Ar), 6.68 (d , 2H, H-Ar), 6.91-7.03 (m, 2H, H-futyl, H- Ar), 7.13-7.73 (m, 7H, H-furyl, H-Ar), 7.94 (d, 1H, H-furyl), 8.05 (d, 1H, CH quinoline), 8.11 (d, 1H, CH quinoline), 9.62 (s, 1H, CH quinoline), 12.16 (s, 1H, COOH). 13C NMR (125 MHz, CDCl3 δ, ppm): 39.98 (1C, CH2-CH), 58.11 (1C, CH2-CH), 110.46 (1C, CH=C-O), 112.70 (1C, CH=CH-O), 113.55 (2C, Ar-C), 113.95 (2C, Ar-C), 122.25 (1C, Ar -C), 127.31 (1C, Ar-C), 128.86 (2C, Ar-C), 129.24 (2C, Ar-C), 133.12 (1C, Ar-C-C), 142.08 (1C, CH-O-C), 142.21 (1C, CH-O-C), 143.21 (1C, Ar-C), 148.54 (1C, C-N=C), 154.04 (1C, C=N), 166.27 (1C, COOH). MS (EI, m/z (%)): 527.54 ([M++2], 10.1), 526. 46 ([M++1], 22.5), 525.18 (M+, 11.3), 391.14 (M+- C8H7O2, 100). 2-(Furan-2-yl)-6-(5-(furan-2-yl)-4, 5-dihydro-1H-pyrazol-3- yl)-3-phenylquinoline-4-carboxylic acid (14): Color: Beige crystals. Yield: 0.41 g, 68%. M.p.: 167-169 °C. FT-IR (KBr, ν, cm- 1): 3358 (NH), 2926 (C-H) (CH2), 1675 (C=O) (acid), 1599 (C=C), 1502 (C=N), 1215 (C-O). 1H NMR (500 MHz, CDCl3, δ, ppm): 3.65-3.70 (dd, 1H(A), CH2, dd, 1H(B), CH2) 4.10-4.15 (dd, 1H(X), -CH), 6.23-6.32 (m , 3H, H-furyl ring), 7.24-7.36 (m, 3H, H-Ar), 7.69-7.78 (m, 4H, H-furyl , H-Ar), 7.96 (d, 1H, H-furyl), 8.06 (d, 1H, CH quinoline), 8.77 (d, 1H, CH quinoline), 9.95 (s, 1H, CH quinoline), 10.11 (s, 1H, NH), 12.35 (s, 1H, COOH). 13C NMR (125 MHz, CDCl3 δ, ppm): 39.95 (1C, CH2-CH). 51.01 (1C, CH2-CH), 110.56 (1C, CH=C-O), 112.51 (1C, CH=CH-O), 127.32 (1C, Ar-C), 128.34 (2C, Ar-C), 129.77 (2C, Ar-C), 133.44 (1C, Ar-C-C), 141.93 (1C, CH-O-C), 144.45 (1C, Ar-C), 148.52 (1C, C- N=C), 155.74 (1C, C=N), 166.21 (1C, COOH). MS (EI, m/z (%)): 451.09 ([M++ 2], 32.2), 450.02 ([M++1], 12.9), 449.11 (M+, 35.18) 437.14 (M+-NH, 10.6). 6-(1-Carbamoyl-5-(furan-2-yl)-4, 5-dihydro-1H-pyrazol-3- yl)-2-(furan-2-yl)-3-phenylquinoline-4-carboxylic acid (15): Color: Beige crystals. Yield: 0.38 g, 64%. M.p.: 155-157 °C. FT- IR (KBr, ν, cm-1): 3360 (NH), 2951 (C-H) (CH2), 1703 (C=O) (acid), 1674 (C=O) (amide), 1603 (C=C), 1513 (C=N), 1216 (C- O). 1H NMR (500 MHz, CDCl3, δ, ppm): 3.67-3.70 (dd, 1H(A), CH2, dd, 1H(B), CH2), 4.10-4.15 (dd, 1H(X), CH), 6.66 (d, 1H, H- furyl), 6.69-6.72 (m, 3H, furyl, NH2), 7.25-7.78 (m, 8H, H-furyl, H-Ar), 7.96 (d, 1H, H-furyl), 8.06 (s, 1H, CH quinoline), 8.10 (d, 1H, CH quinoline), 9.61 (s, 1H, quinoline), 12.46 (s, 1H, COOH). 13C NMR (125 MHz, CDCl3 δ, ppm): 39.89 (1C, CH2-CH), 56.76 (1C, CH2-CH), 110.85 (1C, CH=C-O), 112.51 (1C, CH=CH-O), 127.32(1C, Ar-C), 128.34 (2C, Ar-C), 129.77 (2C, Ar-C), 133.44 (1C, Ar-C-C), 141.93 (1C, CH-O-C), 144.45 (1C, Ar-C), 148.52 (1C, C-N=C), 155.74 (1C, C=N), 166.21 (1C, COOH). MS (EI, m/z (%)): 494.06 ([M++2], 3.5), 493.11 ([M++1], 2.8), 492.08 (M+, 4.2), 434.08 (M+-N2H2CO, 10.6). 2.6. General method for synthesis 1,4-oxazepines derivatives (8 and 16) A mixture of 0.01 mol of α,β-unsaturated carbonyl (2 or 10), 0.01 mol of monoethanolamine dissolved in 25 mL of ethanol and 0.5 mL of ethanolic sodium hydroxide (0.1 mol) was added. The reaction mixture was heated under reflux for 4 h. TLC monitoring was extensively done. The product when cool was poured in ice-cold water. The solid mass which separated out was filtered washed with water and recrystallized from ethanol yield compound 8 and 16 (Scheme 2). 2,3-Diphenyl-6-(7-phenyl-2,3,6,7-tetrahydro-1,4-oxazepin-5- yl)quinoline-4-carboxylic acid (8): Color: Pale yellow crystals. Yield: 0.40 g, 67%. M.p.: 139-141 °C. FT-IR (KBr, ν, cm-1): 3263 (OH), 2978 (C-H) (CH2), 1682 (C=O) (acid), 1601 (C=C), 1505 (C=N), 1216 (C-O-C). 1H NMR (500 MHz, CDCl3, δ, ppm): 3.34- 3.39 (dd, 1H(A), CH2, dd, 1H(B), CH2 ), 3.61 (t, 2H,-CH2), 3.78 (t, 2H,-CH2), 4.93 (dd, 1H(X), CH), 7.17-7.48 (m, 5H, H-Ar), 7.78- 7.61 (m, 6H, H-Ar), 7.97-8.01 (m, 4H, H-Ar), 8.22 (d, 1H, CH quinoline), 8.54 (d, 1H, CH quinoline), 9.95 (s, 1H, CH quinoline), 12.41 (s, 1H, COOH). 13C NMR (125 MHz, CDCl3 δ, ppm): 30.96 (1C, CH2CHO), 63.34 (1C, CH2-O), 127.71 (2C, Ar- C), 127.90 (2C, Ar-C), 128.23 (1C, Ar-C), 128.54 (2C, Ar-C), 128.80 (1C,Ar-C), 128.97 (2C, Ar-C), 129.04 (2C, Ar-C), 129.38 (1C, CH-CH-CN), 133.44 (1C, C-COOH), 141.21 (1C, Ar), 166.40 (1C, COOH). MS (EI, m/z (%)): 500.12 ([M++2], 1.8), 499.11 ([M++1], 5.4), 498.07 (M+, 10.4), 453.12(M+-C2H4O, 100). 2-(Furan-2-yl)-6-(7-(furan-2-yl)-2,3,6,7-tetrahydro-1, 4-oxa zepin-5-yl)-3-phenylquinoline-4-carboxylic acid (16): Color: Brown crystals. Yield: 0.40 g, 67%. M.p.: 225-227 °C. FT-IR (KBr, ν, cm-1): 3387 (OH), 2921 (C-H) (CH2), 1692 (C=O) (acid), 1598 (C=C), 1509 (C=N), 1227 (C-O-C). 1H NMR (500 MHz, CDCl3, δ, ppm): 3.25-3.35 (dd, 1H(A), CH2, dd, 1H(B), CH2 ), 3.64 (t, 2H,-CH2), 3.83 (t, 2H,-CH2), 4.91-5.01 (dd, 1H, 1H(X)-CH), 6.67-6.79 (m, 2H, 2H-furyl), 7.31-7.69 (m, 8H, H-furyl, H- Ar),7.96 (d, 1H, H-furyl), 8.03 (d, 1H, CH quinoline), 8.08 (d, 1H, CH quinoline), 9.61 (s, 1H, CH quinoline), 12.35 (s, 1H, COOH). 13C NMR (125 MHz, CDCl3 δ, ppm): 30.96 (1C, CH2CHO), 45.44 (1C, CH2-N), 58.71 (1C, CH2-O), 110.86 (1C, CH=C-O), 112.43 (1C, CH=CH-O), 127.31 (1C, Ar-C), 128.36 (2C, Ar-C), 129.52 (2C, Ar-C), 134.11 (1C, Ar-C-C), 142.93 (1C, CH- O-C), 144.46 (1C, Ar-C), 146.59 (1C, C-N=C), 166.22 (1C, COOH). MS (EI, m/z (%)): 480.11 ([M++2], 17.2), 479.10 ([M++1], 8.5), 498.07 (M+, 11.5), 437.14 (M+- C2H4O, 100). 3. Results and discussion The starting product structure of quinoline in this study has been synthesized by Doebner reaction which is a condensation reaction between phenyl pyruvic acid (a), primary aryl amines (b) and aldehydes (c) in absolute ethanol to form 2,3-diaryl-quinoline-4-carboxylic acid (1 and 9) (Scheme 1) [15]. The α,β-unsaturated carbonyls (2 and 10) were obtained in good yields by the Claisen-Schmidt condensation of the 6-acetyl-2,3-diaryl-quinoline-4-carboxylic acid derivatives and the substituted benzaldehydes in the base (NaOH) catalyzed and ethanol (Scheme 1) according to the literature [16]. The treatment of α,β-unsaturated carbonyls (2 and 10) with urea derivatives, hydrazine derivatives or monoethanol- amine to yield pyrimidinone/thione [17], pyrazoline [18], and oxazepine [19] heterocyclic rings, respectively (Scheme 2) in reflux temperature was monitored by TLC techniques. All chemical reagents are obtained from commercial suppliers and used without further purification [20]. The structure of the above-mentioned compounds was confirmed by IR, NMR and MS spectral data. The formation of quinoline acid (1 and 9) was confirmed by the peak at ~3250 cm-1 in IR spectrum which is due to the OH stretching of carboxylic acid. A band at ~1670 cm-1 is due to C=O stretch of the acid group [21] and other band for C=O in acetyl group at ~1680 cm-1. 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.1.57-63.1816 62 Hajalsiddig and Saeed / European Journal of Chemistry 10 (1) (2019) 57-63 1 N 2 N 3 HX HBHA 4 5 Figure 1. Carbon numbering of pyrazoline ring. 1 O 2 3 4 N 5 6 7 HB HAHx Figure 2. Carbon numbering of 1,4-oxazepine ring. The 1H NMR spectrum of compounds 1 and 9 showed doublet signals at δ 8.22/8.22 and 8.41/8.42 ppm and singlet at δ 9.45/9.66 ppm is due to quinoline-3H proton. The mass spectrum of compounds 1 and 9 showed a molecular ion peak at M+, which is in agreement with the molecular formula. The IR spectra of all α,β-unsaturated carbonyls (2 and 10) showed the characteristic peaks of particular carbonyl functional groups of enones in the region of ~1672-1682 cm-1, and ~3060-3049 cm-1 stretching vibration for H-C bond of Cα=Cπ. The 1H NMR spectra of α,β-unsaturated carbonyls showed characteristic of signals for α,β-protons at δ 7.22-8.10 ppm, this refers to the effect of resonance of the phenyl rings that bonded to β-carbon atom. The 13C NMR spectra assignment of carbon atoms presented in α,β-unsaturated carbonyl derivatives showed the characteristic peak related to the α-C atom around δ ~131.25-134.84 ppm which was more deshielded than that of β-C atom approximately at δ ~119.99- 121.69 ppm. Mass spectra of α,β-unsaturated carbonyls, showed the M+ consistent with their molecular formula of α,β- unsaturated carbonyls. The structure of the pyrimidinones and pyrimidinthiones characteristic by IR spectra which showed the disappearance of two absorption bands and appearance of new absorption bands for NH, C=O and C=S groups around 3015-3210 cm-1, ~1672 and ~1365 cm-1, respectively. The 1H NMR spectrums of compounds 3, 4, 11 and 12, showed the singlet signal at δ 5.73-5.96 ppm due to the proton of CH-pyrimidinone and at δ 6.17 ppm for CH-pyrimidinthione. Also, singlet broad signal one proton of NH group appeared as δ 10.02 ppm. Further, 13C NMR spectra exhibited confirmatory signals of the methyl carbon C5 around δ 101.05-112.12 ppm. Mass spectra exhibited molecular ion peak [M++2], appeared at different intensities, and confirmed the exact mass or molecular weights of the examined compounds 3, 4, 11 and 12. In the IR spectra of pyrazolines (5, 6, 7, 13, 14 and 15) appeared strong band at 1501-1520 cm-1 for C=N stretching vibration, beside the appearance of above bands, the most important evidence for the formation of 2-pyrazoline is the disappearance of carbonyl group band at 1672-1682 cm-1 special for the α,β-unsaturated carbonyl moiety. The 1H NMR spectra of pyrazolines showed characteristic signals corresponding to the protons of C4 and C5 of 2-pyrazoline ring; they appearance of three doublet to doublet (dd) signals approximately at δ 3.63-5.05 ppm for each compound. The ABX type spin system pattern [22] of proton appeared as a doublet of doublets due to vicinal coupling with the two magnetically non-equivalent protons (HA and HB) of methylene at position 4 and methine proton (HX) at position 5 in pyrazoline ring. The 13C NMR spectra of pyrazolines, showed three signals approximately at δ 63.31-63.29, 39.95-41.27, 51.01-58.11 ppm belongs to C3, C4 and C5 for pyrazoline carbons (see Figure 1 for the carbon numbering). Mass spectra of pyrazolines showed the [M++2] confirmed with their molecular formula of pyrazoline derivatives. The IR spectra of 1,4-oxazepines (8 and 16) showed typical peaks at ~1505-1509 cm-1 for C=N stretching vibration and at ~1216-1227 cm-1 for ethers. These peaks confirmed us that 1,4-oxazepines rings were formed. 1H NMR spectra of compounds 8 and 16 showed similar effects on the chemical shifts of the pyrazoline protons signal of three doublet to doublet (dd) signals approximately at δ ~3.25-5.01 ppm for each compound due to the ABX spin pattern of two protons of methylene at position 6 and methine proton at position 7 in 1,4-oxazepine ring. The characteristic two triplet signals at δ ~3.61-3.63 and 3.73-3.83 ppm for each methylene protons in position 2 and 3 in 1,4-oxazepines ring. The 13C NMR spectra of 1,4-oxazepines showed the signal for C2, C3 and C6 of the seven-membered ring appear in the range of δ 58.71, 45.44 and 30.96 ppm, respectively (see Figure 2 for the carbon numbering). Mass spectra of compounds 8 and 16 appear peak [M++2] and M+ these were consistent with product structures. 4. Conclusion In this manuscript, we present the successful synthesis of some new heterocyclic compounds of 2,3-diaryl-quinoline-4- carboxylic acid as the core with good yields. The detail assignments of these compounds have been discussed by IR, 1H NMR, 13C NMR, and LC-MS spectra. Synthesis results of this work gave pyrimidinone/thione, pyrazoline, and oxazepine rings from α,β-unsaturated carbonyls could be useful for other chemists working on the field of heterocycles quinoline synthesis. Disclosure statement Conflict of interests: The authors declare that they have no conflict of interest. Author contributions: All authors contributed equally to this work. Ethical approval: All ethical guidelines have been adhered. Sample availability: Samples of the compounds are available from the author. 2019 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.10.1.57-63.1816 Hajalsiddig and Saeed / European Journal of Chemistry 10 (1) (2019) 57-63 63 ORCID Tawassl Tajelsir-Hassan Hajalsiddig http://orcid.org/0000-0001-8053-6339 Ahmed Elsadig Mohammed Saeed http://orcid.org/0000-0002-7317-8040 References [1]. Kannappan, N.; Reddy, BS.; Sen, S.; Nagarajan, R.; Dashpute, S. J. Appl. Chem. Res. 2009, 9, 59-68. [2]. Marella, K.; Tanwar, O. P.; Saha, R.; Ali, M. R.; Srivastava, S.; Akhter, M.; Shaquiquzzaman, M.; Alam, M. M. S. Pham. J. 2013, 21, 1-12. [3]. Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles, 2nd edition, Wiley-VCH, Weinheim, 2003. [4]. 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Introduction 2. Experimental 2.1. Instrumentation 2.2. General method for synthesis 2, 3-diaryl-quinoline-4-carboxylic acid derivatives (1, 9) 2.3. General method for synthesis α,β-unsaturated carbonyl derivatives (2 and 10) 2.4. General method for synthesis 2-pyrimidinone/thiones derivatives (3, 4, 11 and 12) 2.5. General method for synthesis pyrazoline/pyrazoline-1-phenyl/pyrazoline-1-carboxamide derivatives (5, 6, 7, 13, 14 and 15) 2.6. General method for synthesis 1,4-oxazepines derivatives (8 and 16) 3. Results and discussion 4. Conclusion Disclosure statement ORCID References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField15: PrintField16: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: PrintField25: PrintField26: