Green protocol for thesynthesis of 1, 8-dioxodecahydroacridines using citric acid as organocatalyst Monika Patil1, ShrikrishnaKarhale1, Ananda Kudale 1 Arjun Kumbhar2,Sagar More2, Vasant Helavi*11Department of Chemistry, RajaramCollege, Kolhapur 416004, Maharashtra, India.2Department of Chemistry, P. D. V.P. College, Tasgaon 416312, Maharashtra, India.
E-mail:[email protected]*Corresponding author: Tel.: +91231 2537840; fax: +91 231 2531989.
Graphical Abstract: Green protocol for thesynthesis of 1, 8-dioxodecahydroacridines using citric acid as organocatalyst Monika Patil1,Shrikrishna Karhale1, Ananda Kudale 1 Arjun Kumbhar2,Sagar More2, Vasant Helavi*1Abstract:A simple, efficient and an environmentally benign route have been described forsynthesis of 1, 8-dioxodecahydroacridine via Hantzsch condensation of aldehydesand ammonium acetate with cyclic 1, 3-dicarbonyl compound using citric acid asan inexpensive green additive in ecological safe solvent. Utilization of cheap,safe reagent and solvent, cleaner reaction profile, straightforward work-upprocedure and good to excellent yield are the remarkable features of thismethod._____________________________________________________M. Patil, S. Karhale,A. Kudale,A. Kumbhar, S.
More, V. Helavi*1Department of Chemistry, Rajaram College, Kolhapur,416004, M.S., India2Department of Chemistry, P. D. V.
P. College, Tasgaon,416312, M.S., India.
E-mail: [email protected]*Correspondingauthor. Tel.: +91 231 2537840; fax: +91 231 2531989. Introduction: As ourenvironment is endowed by nature, needs to be protected from growing productionof large amount of waste and toxic by-products which sequentially leads to chemicalpollution. Therefore, synthetic chemists have earned tremendous interest todevelop relatively safe technologies which play a vital role in green chemistry.
By concerning above fact, establishing newer chemical transformations should satisfygreen principles such as non-toxicity, non-flammability, easy work-up, eco-friendlymedium, separation and recycling of the catalysts. Since, from the last decade moreefforts were devoted towards the design of an environment friendly chemicalsynthesis with respect to reagents, environmentally benign solvents that couldbe easily biodegradable 1, 2. Multi-component reaction (MCR) strategies whichhave been widely used in the convergent synthesis of complex organic moleculesfrom simple and readily available starting materials with high atom economy andhigh selectivity is one of the tool to achieve both economic and environmentalgoals. Therefore, synthesis of heterocyclic compounds with significantbioactivities with MCR support is an immensely important pursuit in organicsynthesis. Synthesis ofacridinesis an enormous area of interest due to polyfunctionalized group with wide rangeof biological activities as well as an ecological point of view 3. Amongthem, 1, 8-dioxodecahydroacridines is an important class of aza-heterocycles inwhich a phenyl substituted pyridine ring is fused with two cyclohexanone rings.These structure contains 1, 4-dihydropyridine (1,4-DHP) as a parent nucleuswhich acts as fluorescent probes in bioanalytical chemistry 4 and also used aspotential drug candidates for the treatment of cardiovascular diseases. Some ofthe representative compounds of this class are used in dye-sensitized solarcells and also in the preparation of blue light-emitting devices 5-6.
Inaddition, the 9-aryl-decahydroacridine-1,8-dione derivatives have been widelyemployed as DNA intercalator, SIRT1 inhibitors, calcium and potassium channelmodulators 7-8. Several studies reveal that these heterocycles exhibits copiousmedicinal applications which include antitumor, calcium -blockers, antileukimic,antifungal, anticancer, anti-atherosclerotic, and bronchodilator 9-13. Theseare also used as, laser dyes, chemosensors and initiators in photopolymerization process. These derivatives are important due to their structuralsimilarity with the coenzyme nicotinamide adenine dinucleotide (NADH), whichacts as coenzyme in biological systems. Themost common route for the synthesis of 1,8-dioxodecahydroacridines includescondensation of diverse aldehydes, dimedone or cyclic 1, 3-dicarbonyl compoundswith various nitrogen source such as ammonium acetate, urea, ammoniumhydroxide, ammonium bicarbonate, and hydroxylamine 14-18.
A variety ofcatalysts such as sulfonated polyethylene glycol(PEG-OSO3H), Silzic (SiO2-ZnCl2), silicaboron-sulfuric acid, Proline, Zn(OAc)2, nano nickel cobalt ferrite(Ni0.5Co0.5Fe2O4),Carbon based solid acid, Bronsted acidic imidazolium salts, Ascorbic acid,Acetic acid, Tris(pentafluorophenyl)borane/B(C6F5)3,Silica-Supported polyphosphoric acid,ammonium chloride, Silica-supported preysslernanoparticles 19-32 etc have been reported to accomplish thistransformation. However, most of these reported methodologies have certain drawbacks suchas use of toxic and corrosive solvent, use of expensive chemicals, tediouspreparation of catalyst, prolonged reaction times, tedious work-up, harshreaction conditions and low yields of the desired product. Therefore, a great demandstill exists for utilization of an efficient, simple and eco-friendly processespecially by using organocatalyst is highly desirable. Citricacid (2-hydroxy-propane-1, 2, 3-tricarboxylic acid) is a weak organic acid withthe formula C6H8O7 and was first isolated andcrystallized from lemon juice in 1784. It is found as natural preservative andantioxidant in variety of citrus fruits orange, lemon, pineapple, peach andpear.
This organic acid is a nearly universal intermediate product ofmetabolism. Furthermore, citric acid is also used for the preparation of saltand form complex with many metals such as magnesium, iron, manganese, calciumand copper. Widespread presence, non-toxic nature and chemical stability ofthis acid, it has been used as sequestering in industrial process, as softenerin detergent, as an anticoagulant blood preservative and as a complexing agentin metal treatment. Other industrial and pharmaceutical applications of citricacid include antioxidant in cosmetics, cleaning, buffering.
Despite its hugeindustrial and pharmaceutical importance, only a few reports exemplify its catalyticapplication in organic synthesis. As part of our research work in the development of sustainablemethodologies for the synthesis of bioactive moiety 33-38, herein we reportgreen protocol for the synthesis of 1,8-dioxodecahydroacridinesfrom one pot multi-component reactionof dimedone and NH4OAc with diverse aryl aldehydes in the presenceof inexpensive and highly efficient citric acid as organocatalyst (Scheme 1). Scheme1: Citric acidcatalyzed multi-component synthesis of 1, 8-dioxodecahydroacridines. Result anddiscussion:We optimized the reaction conditions such as effectsof solvents and catalyst. Initially to optimize the solvents efficacy, thereaction of benzaldehyde (1 mmol), dimedone (2 mmol), and ammonium acetate (1.
2mmol) in presence of citric acid (2 mmol) was selected as a model reaction (Scheme1). In pilot experiment, the reaction was carried out in a variety of solventswater, ethanol, ethanol:water, methanol, acetonitrile, dichloroethane and tolueneas shown in Table 1. Thebest result was obtained by the reaction using ethanol providing excellentyield (89%) of the desired product (Table1, entry 2). The reaction proceeded scarcely in water, ethanol:water,methanol, acetonitrile, dichloroethane and toluene providing moderate yields ofanticipated products in comparatively prolonged reaction time (Table 1, entries 1, 3-7).Table 1:Optimization of solvent for synthesis of 1, 8-dioxodecahydroacridinea Entry Reaction Condition Time (min) Isolated Yieldb (%) 1 Water/ Reflux 240 70 2 Ethanol/Reflux 150 89 3 Ethanol:Water/ Reflux 200 80 4 Methanol/ Reflux 300 72 5 Acetonitrile/ Reflux 360 68 6 Dichloroethane/ Reflux 400 55 7 Toulene/ Reflux 390 65 aReactionconditions: Dimedone (2 mmol), benzaldehyde (1 mmol), NH4OAc (1.
5mmol) and citric acid monohydrate as green additive in various solvent at reflux.bIsolated yields. Ournext task was to optimize the catalyst loading. For this, we have carried the modelreaction under optimized conditions by varying the quantity of citric acid assummarized in Table 2. It was foundthat the quantity of catalyst played crucial role on the product yield. Whenthe quantity of citric was increased, the yield of target product was elevatedsignificantly (Table 2, entries 1-3)and maximum yield of the product obtained when 2 mmol of citric acid was used (Table 2, entry 4) Further increase inquantity of citric acid did not influence on yield of the product (Table 2, entry 5). With this result in hand, we havestudied the effect of temperature on model reactioncondition by conducting model reaction at 100°C and at room temperature but thereaction proceeded long time with unsatisfactory result.Table2 Optimizationof catalyst amount for the synthesis of 1, 8-dioxodecahydroacridinea Entry Citric Acid (mmol) Time (min) Isolated Yield (%) 1 – 150 – 2 1 150 68 3 1.
5 150 78 4 2.0 150 89 5 3.0 150 89 aReactionconditions: Dimedone (2 mmol), benzaldehyde (1 mmol), NH4OAc (1.5mmol) and citric acid in ethanol at reflux.
Table3:synthesis of 1, 8-dioxo-decahydroacridine derivatives.a Entry Aldehydes (2) Product Time(min) Yield (%) a Benzaldehyde 4a 150 89 b 4-Nitrobenzaldehyde 4b 100 90 c 4-Chlorobenzaldehyde 4c 160 87 d 4-Bromobenzaldehyde 4d 180 85 e 4-Cyanobenzaldehyde 4e 200 74 f 4-Hydroxybenzaldehyde 4f 160 83 g 4-Methoxybenzaldehyd 4g 210 90 h 4-Methylbenzaldehyde 4h 130 79 i 3,4,5-Trimethoxybenzaldehyde 4i 230 80 j Thiophene-2-carbaldehyde 4j 240 81 k Isopropanaldehyde 4k 300 45 aReaction conditions:Dimedone (2 mmol), aryl aldehyde (1 mmol), NH4OAc (1.5 mmol) andcitric acid in ethanol at reflux.Afterthe optimization of reaction conditions, we evaluate the scope and generalityof protocol by reacting dimedone, NH4OAc with diverse aromatic aldehydes.The results are shown in Table 3. Thereaction proceeded smoothly in all the cases to afford the desired 1,8-dioxodecahydroacridinein good to excellent yields. It is worthy to note that both electron rich andelectron deficient aromatic aldehydes reacted efficiently with good chemicalreactivity.
However, the reaction with aliphatic aldehyde, the time wasprolonged and the yield of the product was very low. Fig 1:Reusability of citric acid synthesis of 1, 8-dioxo-decahydroacridineWe have examined the reusability of citric acid forthe model reaction. After completion of the reaction, the product was separatedand resulting filtrate extracted by chloroform. The catalyst was separated fromaqueous layer and dried under vacuum. The recovered citric acid was used forsimilar reaction and as it is shown in graph the catalyst could be reusedwithout significant loss of activity (Fig 1).The plausible mechanism for 1,8-dioxodecahydroacridines is depicted in scheme2. First the citric acid promote for enolization of 1, 3-diketone moleculeand convert aldehydes into suitable electrophile by protonation and theknoevengel adduct A formed byreaction of enol form of 1, 3-diketone and the aldehydes.
Then, A may undergo Michael addition withanother molecule of dimedone in its enol form influence by citric acid to yieldintermediate B. The resultingintermediate reacts with ammonium acetate to yield imine which undergoesan intramolecular cyclization and dehydration to yield the estimated product C. Scheme 2: Proposedreaction mechanism for synthesis of 1,8-dioxodecahydroacridines Table4:Effect of various catalysts on synthesis of 1, 8-dioxodecahydroacridines Entry Catalyst Reaction Condition Time (min) Yield (%) References 1 Citric acid (2 mmol) Ethanol/Reflux 150 89 This work 2 Ni0.5Co0.
5Fe2O4 (20 mol %) EtOH:H2O (1:1),Reflux 40 92 24 3 SiO2-ZnCl2 (0.2 g mol %) 100° C 30 70 20 4 B (C6F5)3 (3 mol %) RT 168 80 29 5 PPA-SiO2 (0.02 gm) 100°C 10 93 30 6 Ammonium chloride 120°C 60 87 31 7 SPNP (0.
03 mmol) H2O, reflux 120 91 32 Inorder to show the efficiency and advantages of citric acid with the reportedcatalysts, we have tabulated several results for the synthesis of 1,8-dioxodecahydroacridines in Table 4. It is clear that, citric acid is effective in terms ofyield and reaction times than reported catalysts.Experimental:All chemicals were purchase from local supplier andused without further purification.
Melting points were determined by the opencapillary method and are uncorrected. The IR spectra were measured on BrukerALPHA FT-IR spectrometer in between the frequency range 500-4000 cm-1.The NMR spectra were recorded on Bruker AC (400 MHz for 1H NMR and75 MHz for 13C NMR) spectrometer using TMS as an internal standard.Chemical shifts (d)are expressed in ppm.Generalprocedure for the synthesis of 1, 8-dioxodecahydroacridine derivatives (4a-k):A mixture of dimedone (2 mmol), aldehyde (1 mmol),ammonium acetate (1.2 mmol) and citric acid (2 mmol) in ethanol (4 mL) wasstirred at reflux for appropriate time (Table 3). After complete conversion asindicated by TLC, the reaction mixture was allowed to cool at room temperature,poured onto ice-cold water (20 ml) and stirred continuously for 10 minutes. Theformed solid filtered, washed with cold water and then dried.
The solid was recrystallizedby in ethanol. All the resulting products were purified and characterized byspectroscopic techniques.Selectedspectral data of representative compounds3, 3, 6, 6-Tetramethyl-9-(phenyl)-1, 8-dioxo-decahydroacridine(Table 3, entry a):Mp:193-195°C, 1H NMR (400 MHz, CDCl3) ? (ppm): 7.
45 (s, 1H,NH), 7.65-7.10 (m, 5H, Ar-H), 5.15 (s, 1H, CH), 2.42-2.
17 (m, 8H, CH2),1.12 (s, 6H, CH3), 0.98 (s, 6H, CH3); 13C NMR(75 MHZ, CDCl3) ?: 193.8, 148.3, 136.4, 126.
8, 128.1, 1256.8, 114.3,51.1, 41.3, 34.2, 33.
6, 29.9, 27.6; IR (KBr, cm-1) ? : 3275, 2959,1631, 1368.3, 3, 6, 6-Tetramethyl-9-(4-chlorophenyl)-1, 8-dioxo-decahydroacridine(Table 3, entry c):Mp:295-297 °C, 1H NMR (400 MHz, CDCl3) ? (ppm): 7.66 (s, 1H, NH), 7.
48 (d, J = 9, 2H), 7.38 (d, J = 9, 2H), 5.16 (s, 1H, CH), 2.30-2.13 (m, 8H, CH2), 1.17 (s, 6H, CH3), 0.95 (s, 6H, CH3);13CNMR (75 MHZ, CDCl3) ?: 196.
1, 150.1, 144.9, 132.0, 130.
1, 127.9, 113.2,51.5, 41.
1, 34.4, 33.6, 30.
5, 26.8; IR (KBr, cm-1): 3436, 2954, 1647, 1612, 1365.3, 3, 6, 6-Tetramethyl-9-(4-cynophenyl)-1, 8-dioxo-decahydroacridine(Table 3, entry e):Mp:324-326°C, 1H NMR (400 MHz, CDCl3)? (ppm): 0.96 (s, 6H, CH3), 1.13 (s, 6H, CH3), 2.19 (d, J?16.5 Hz, 2H), 2.
28 (d, J?16.5 Hz, 2H), 2.26(d, J?16.5 Hz, 2H), 2.43 (d, J?16.
5 Hz, 2H), 5.11 (s, 1H, CH), 5.91 (s, 1H, NH),7.46 (d, J?8.3Hz, 2H, Ar-H), 7.52 (d, J?8.3Hz, 2H, Ar-H); 13C NMR (75 MHZ, CDCl3) ?: 194.
8, 148.7, 146.1, 130.2,129.5, 120.7, 112.9, 50.4, 32.
9, 32.0, 30.5, 29.
1, 26.6; ); IR (KBr): 3321, 2955, 2233, 1631, 1491 cm-13, 3, 6, 6-Tetramethyl-9-(4-methoxyphenyl)-1, 8-dioxo-decahydroacridine(Table 3, entry g):Mp:270-272°C, 1H NMR (400 MHz, CDCl3)? (ppm): 8.82 (s, 1H, NH), 7.12 (d, J = 8.
6 Hz, 2H), 6.64 (d, J = 8.6 Hz, 2H), 4.83(s, 1H, CH), 3.65 (s, 3H,O-CH3), 2.35 (d, J= 17.
0 Hz, 1H), 2.24 (d, J = 16.3 Hz, 1H), 2.10 (d, J =15.9, 1H), 1.98 (d, J = 16.
2 Hz, 1H), 1.01 (s, 6H, CH3),0.98 (s, 6H, CH3);13CNMR (75 MHZ, CDCl3)?:192.4, 154.6, 149.1, 138.9, 128.6, 112.
8, 111.8, 54.6, 51.
8, 32.2, 30.3, 28.9,26.
5.; IR (KBr, cm-1): 3448, 2954, 1643, 1612, 1365, 1141.3, 3, 6, 6-Tetramethyl-9-(4-methylphenyl)-1, 8-dioxo-decahydroacridine(Table 3, entry 1):Mp: 271-273°C, 1H NMR (400 MHz, CDCl3)? (ppm): 11.9 (s, 1H, NH), 7.09 (d, J = 9, 2H), 6.
98 (d, J = 9, 2H), 5.50 (s,1H, CH), 2.29 (s, 3H, CH3), 2.19-2.47 (m, 8H, CH2), 1.
22 (s, 6H, CH3),1.09 (s, 6H, CH3); 13C NMR (75 MHZ, CDCl3) ?:190.6, 135.5, 135.
1, 129.3, 128.9, 126.5, 117.7, 47.
2, 46.6, 32.5, 31.3, 29.8,27.
4; 20.9; IR (KBr, cm-1) : 2958, 2877, 1569, 1369.Conclusion:In this work,the reported method offers simple, and economically viable one-pot method for synthesisof decahydroacridine-1, 8-diones derivatives via Hantzsch condensationof various aldehydes, ammonium acetate with cyclic 1, 3-dicarbonyl compound using commercially available, inexpensivecitric acid as a green additive. Some important superiorities of this methodare use of inexpensive reagents, absence of toxic effluents, use of greensolvent, easy workup and operational simplicity In addition, employment ofgreen, inexpensive, eco-friendly and commercially available additive make thisprocedure very attractive in modern synthetic methodologies. References: (Research on chemical intermediate)1 P.
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