Novel Dihydroquinoline Derivatives Facile Synthesis

Novel Dihydroquinoline Derivatives Facile SynthesisFacile synthetic thinking of novel dihydroquinoline-3,3-dicarbonitriles in the presence of glacial aceticacid as atom smasher at a lower place solvent-free conditionsMasoud Nasr-Esfahani* and Elham Kanaani department of Chemistry, Yasouj University, Yasouj, IranAbstr processA series of novel dihydroquinoline derivatives were synthesized using malononitrile, 2-aminobenzoic acid and benzaldehydes in the presence of a catalytic amount of acetic acid, without the use of any extra co-catalyst, under solvent-free conditions. The chemical reaction is characterized by high efficiency, easy workup, simple purification of the products and availability of catalyst.Keywords Dihydroquinoline derivatives, Acetic acid, Malononitrile, 2-Aminobenzoic acid, solvent-freeIntroductionHeterocyclic compounds including nitrogen, have an important role in organic chemistry. Among these compounds, the quinoline derivatives have attracted great attention be cause of their application in biological and pharmacological fields. They act as antimalarial,1-3 anti-psychotic,4 antihypertensive,5 anti-parasitic,6 anthelmintic,7 antitubercular,8 antiasthmatic,9 antifungals,10,11 anticancer,12 anti-inflammatory,13 anti-HIV,14 anti-AIDS,15 and antineoplastic.16A few promising compounds with quinoline ring system be shown as 13 compounds (Fig. 1). Furthermore, quinoline derivatives can be used in the implication of fungicides, biocides, alkaloids and flavoring agents,17 as well as these compounds find use in manufacturing a wide variety of food and lake colors. They could generate a sharp green electroluminescence and have the high quantum efficiency of emission in the blue and the green region.18 Therefore, in regard to these observations and importance of pharmaceutical and biological of these compounds, herein we study the solvent-free synthesis of novel dihydroquinoline derivatives in presence of glacial acetic acid as catalyst.In the contex t of green chemistry, the development of clean technologies is very important in organic and medicinal chemistry. The use of available and nonvenomous catalysts and replacing solution reactions with solvent-free ones ar whatever cases that can help reduction and elimination of harmful effects of chemical reactions.19The volatile nature and toxicity of many organic solvents that are astray used for organic reactions have propounded a serious threat to the environment. Therefore, in recent years, the design of solid-state reaction has received much attention from the eco-friendly synthesis viewpoint. Solvent-free techniques represent several significant synthetic benefits including savings in money, cadence and products, and simplicity of the experimental procedure and work-up technique.In recent times application of nontoxic catalysts such as glacial acetic acid in chemical reactions has been an area of interest. Acetic acid is an brilliant polar protic solvent and can act as a mild and competent catalyst for the promotion of the organic reactions. Other factors that stimulate the use of acetic acid include the price of catalyst and simplicity of the work-up procedure.In this research, we report the synthesis of 4-oxo-2-aryl-1,2-dihydroquinoline-3,3(4H)-dicarbonitriles, that involves two steps, in presence of glacial acetic acid under solvent-free conditions. AcOH is an efficient, inexpensive and available acid and in recent decades has been recognizing as a mild catalyst in organic synthesis.20Results and DiscussionIn continuation of our studies in the development of the synthetic methodologiesfor the preparing of fine chemicals and cyclic compounds of biological importance,21-25 herein, we were interested in reporting the synthesis of novel dihydroquinoline derivatives in the presence of the glacial acetic acid as a mild and efficient catalyst. This synthesis involves two steps firstly, 2-(2-aminobenzoyl) malononitrile mediate (6) was synthesized vi a the glacial acetic acid-catalyzed reaction of 2-aminobenzoic acid (4) with malononitrile (5) under solvent-free condition. Subsequently, the novel dihydroquinoline derivatives (8)were prepared by addition of benzaldehyde derivatives (7) to the mixture reaction and attack on the intermediate 6 and followed by intermolecular cyclization ( turning away 1, Table 1).The main advantage ofthis reaction that was carried out with AcOH is that the percentage of peripheral products was low and the recrystallization was overly much easier.The 1H NMR spectrum of 8b showed a singlet identified as CH ( = 4.263 ppm), and a signal at 7.831 ppm for NH group. The signals appearing in the 7.308-8.197 ppm are assigned for resonant peal protons. The proton decoupled 13CNMR spectrum of 8b compound exhibited 14 distinct resonances that confirmed the proposed structure.The infrared spectra (IR) of these compounds show NH bonds appearing at 3388-3453 cm-1. The bands found at 2210-2229 cm-1 are attribut ed to the CN groups. The intense bands appearing at 1695-1700 cm-1 are assigned to carbonylic groups. The peaks in the region of 1025-1350 cm-1 are assigned for (C-N) stretching vibration.The proposed mechanism in which acetic acid has catalyzed this conversion was depicted in Scheme 3. Initially, the proton of acetic acid activates carbonyl group of 2-aminobenzoic acid (3) to achieve intermediate 9 and thus increases the electrophilicity carbonyl carbon of acid. In the following, nucleophilic addition of intermediate 10 was done by intermediate 9 and following the loss of H2O intermediate 6 was produced. In the next step, with the addition of an aromatic aldehyde to the reaction mixture, the carbonyl group of aldehyde was activated by acetic acid to give intermediate 11 thus increases the electrophilicity of carbonyl carbon of aldehyde 7 . The reaction proceeds by nucleophilic addition of the amino group of 6 to the activated aldehyde to afford intermediate 12 and following loss o f H2O intermediate 13 was produced. Finally, with intermolecular cyclization of intermediate 13 the product 8 was produced (Scheme 2).ConclusionsIn summary, a novel class of dihydroquinoline derivatives 8 was obtained using 2-aminobenzoic acid, malononitrile and aromatic aldehydes in presence of AcOH as catalyst under solvent-free conditions. These novel compounds as potentially useful compounds with possible biological and pharmaceutical activities can be applied in various fields such as medicinal and agricultural areas. The most important features of this protocol are an inexpensive and available catalyst, simple purification, easy work-up, with the desired products being isolated in excellent yields.Experimental SectionChemicals and reagents were purchased from Merck, Fluka, and Aldrichchemical companiesand were used without further purification. IR spectra were recorded applying a FT-IR JASCO-680 spectrophotometer in KBr with absorptions in cm-1. The 1H NMR (four hundred MHz) a nd 13C NMR (100 MHz) spectra were recorded on a Bruker 400 MHz Ultrashield spectrometer in DMSO-d6 solution with TMS as an internal standard. Mass spectra were recorded by the Fisons Trio 1000 (70 ev). All melting points were measured on a Barnstead Electrothermal (BI 9300) apparatus in open capillary tubes and all are uncorrected. The progress of the reaction was monitored by thin layer chromatography (TLC).General procedure for the synthesis of dihydroquinoline derivatives using AcOHFirstly, a mixture of malononitrile 5 (1.0 mmol, 0.06 g), 2-aminobenzoic acid 4 (1.0 mmol, 0.14 g) and glacial acetic acid (o.2 ml), was heated at 80 C under solvent-free conditions with nonessential stirring for the 6 h (reactions were monitored by TLC). Subsequently, with the fundamental law of intermediate 6, aromatic aldehyde 7 (1.0 mmol) was added to the reaction mixture, and the mixture was stirred under reflux for the suitable time (reactions were monitored by TLC). After completion of the rea ction, ethyl acetate was added and the obtained mixture filtered and then washed with water. After that, the obtained crude products were recrystallized in ethyl acetate to afford the saturated product in 70-87% yields (table 1). The products were characterized by IR, 1H NMR, 13C NMR and mass spectroscopic methods.2-(4-nitrophenyl)-4-oxo-1,2-dihydroquinoline-3,3(4H)-dicarbonitrile (8a)Brown solid, Mp 238-240 CIR (KBr, cm-1) 3440, 3165, 2225, 1695, 1509, 1417, 1344, 1203, 1160, 833, 572 1H NMR (400 MHz, DMSO-d6) 8.39 (t, 2H, J = 7.8 Hz, aromatic CH), 8.30 (d, 1H, J = 7.6 Hz, aromatic CH), 8.15 (t, 2H, J = 7.8 Hz, aromatic CH), 8.07 (s, 1H, NH), 7.91 (t, 1H, J = 8.4 Hz, aromatic CH), 7.69-7.63 (m, 2H, aromatic CH ), 4.62 (s, 1H, CH) 13C NMR (100 MHz, DMSO-d6) 203.81, 162.54, 149.23, 148.75, 138.52, 131.44, 129.52, 126.17, 124.65, 118.15, 116.19, 111.06, 60.24, 56.02 MS (m/z) 318.1C17H10N4O3+, 293.1 C16H11N3O3+, 246.1 C16H12N3+, 234.1 C16H12NO+, 184.1 C11H8N2O+, 277, 170, 127, 101, 89 , 75.Acknowledgements We are grateful to the Yasouj University for supporting this work.SUPPORTING INFORMATIONExperimental method, IR, 1H NMR, 13C NMR, Mass and MP for this article can be found via the Supplementary Content section of this articles webpage.Broom, A. 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Synthesis of 4-oxo-2-aryl-1,2-dihydroquinoline-3,3(4H)-dicarbonitriles using AcOHEntryRProduct cadence 1 (h)Time 2 (h)Yield (%) aMp (C)8a4-NO26587238-2408 b4- Cl6687201-2048c2,4- Cl26684177-1798d4- Br6874217-2258e4- OMe6977206-2088f4- Me6969140-142a Isolated yield.Scheme 2 Proposed mechanism for the formation of dihydroquinolines 8.