Microwave-assisted Synthesis Of 2-pyridone And 2-pyridone .

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Microwave-assisted synthesis of 2-pyridone and 2-pyridone-basedcompoundsDušan Ž. Mijin, Jelena M. Marković, Danijela V. Brković, Aleksandar D. MarinkovićFaculty of Technology and Metallurgy, University of Belgrade, Belgrade, SerbiaAbstract2-Pyridones are important heterocyclic compounds that are widely used in medical chemistry, and their various derivatives have significant biological and medical applications. Inthis paper, the synthesis of 2-pyridones as well as 2-pyridone-based compounds, such as2-quinolones, using microwave assisted organic chemistry is reviewed. The review isdivided in three parts. In the first part, microwave synthesis of 2-pyridones according tothe type of condensation is discussed. In the second part, microwave assisted synthesis of2-quionolones is listed. At the end of the review several examples of microwave synthesisof other 2-pyridone based compounds (ring fused N-substituted 2-pyridones) are given.REVIEW PAPERUDC 61:54]:547.7/.8:547.824Hem. Ind. 68 (1) 1–14 (2014)doi: 10.2298/HEMIND121204021MKeywords: heterocyclic compounds, medical chemistry, microwave assisted organic chemistry, 2-quinolone ring fused N-substituted 2-pyridones.Available online at the Journal website: http://www.ache.org.rs/HI/Aromatic heterocyclic compounds represent animportant group of compounds due to their biologicaland medical applications. The six-member heterocyclicrings containing nitrogen (e.g., pyridine, pyridone, pyrimidine, piperidine and piperazine) are used in medicinesince they possess certain pharmacological properties.Among them, 2-pyridone compounds are particularlysignificant (Figure 1).2-Pyridone derivatives are especially interestingbecause the 2-pyridone structure is present in manycompounds of natural origin [1], many of which possessbiological activity. Most of these compounds possessantibacterial [2,3], antifungal [4], anti-inflammatory [5],antiviral [6,7], antitumor [8] and antiplatelet [9,10]properties. 2-Pyridone derivatives are used in themanufacturing of paints [11], pigments, additives forfuels and lubricants, acid-base indicators, stabilizers forpolymers and coatings [12]. Due to a variety of pharmacological properties, the 2-pyridone structure isimportant in the pharmaceutical industry [13]. Manymedications contain 2-pyridone structure: cardiotonics(milrinone (Figure 1a) and amrinone (Figure 1b) usedfor the treatment of heart failure [14,15]; and antibiotics (pilicides (Figure 1c) and curlicides) which treatbacterial infections caused by Gram-negative bacteria[16,17]. A derivative of N-phenyl-2-pyridone, perampanel (Figure 1d), acts as a non-competitive and selective antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, and improves motorsymptoms in animal models of Parkinson's disease [18].Correspondence: D. Mijin, Faculty of Technology and Metallurgy,University of Belgrade, Karnegijeva 4, P.O. Box 3503, 11120 Belgrade,Serbia.E-mail: kavur@tmf.bg.ac.rsPaper received: 4 December, 2012Paper accepted: 25 January, 2013It should be noted that 4-pyridone, isomer of2-pyridone, due to mesogenic properties, is used in thesynthesis of liquid crystals [19]. It has antioxidant properties and is used in the treatment of hyperglycemia[20]. 4-pyridone also has the capability of complexationand can be used for the preparation of supramolecularstructures [21]. Methylated N-4-pyridone derivativesare used as intermediates for the synthesis of pharmaceuticals, pesticides, insecticides, fungicides, etc.N-Methyl-4-pyridone is used in the production of compounds that are used to produce images [22].Due to the many applications of the compoundsthat contain 2-pyridone structure, a number of procedures for their synthesis was developed [23,24]. Ageneral procedure for obtaining substituted 2-pyridones is the Guareschi-Thorpe condensation reaction of1,3-dicarbonyl compounds with cyanoacetamide [25,26],which was used for the synthesis of large number ofpyridones [27–29]. Cyclization of cyanoacetamide with1,3-dicarbonyl compounds belongs to the 3-2 type ofcondensation that leads to the formation of pyridonering. The mechanism of the reaction is complex andinvolves Knoevenagel reaction, addition of Michael orPerkin reaction, whereby the degree of enolyzation ofdioxo compounds determines the participation ofMichael addition [30,31]. Also, this type of reaction isused to obtain arylazo pyridone dyes [32–37]. Unlikeconventional conditions (high temperature, polar organic solvents), the newer approach, enzymatically catalyzed synthesis of 2-pyridones, carried under mild reaction conditions, is characterized by high regio- andstereo-selectivity, high purity and final yield of theobtained products [38,39].The conventional way of performing organic synthesis involves heating by external heat sources (e.g.,oil bath). In this way, heat is transferred by conduction,1

D.Ž. MIJIN et al.: MICROWAVE-ASSISTED SYNTHESIS OF 2-PYRIDONE-BASED COMPOUNDSHem. ind. 68 (1) 1–14 re 1. 2-Pyridone compounds which possess physiological activity: a) milrinone, b) amrinone, c) ring fused pyridone with pilicideactivity and d) perampanel.which is a slow and inefficient method of energy transfer, because it depends on the thermal conductivity ofthe materials and the reactor temperature is higherthan the temperature of the reaction mixture. On theother hand, microwave irradiation is an efficient way ofheating where energy is transmitted directly throughinteraction with polar molecules present in the reactionmixture [40,41].Microwave irradiation is not ionizing and does notbelong to harmful radiation. Microwaves have a frequency between 0.3 GHz and 300 GHz, correspondingto wavelengths between 1 cm and 1 m [42]. The mainadvantages of microwave-assisted organic chemistryare the increase of product yields and the reduction ofreaction time [43,44]. The short reaction time and theincreasing number of microwave assisted reactionslead to the application of this technique in the variousfields of industry. For example, the modern pharmaceutical industry requires the creation of a growingnumber of new molecules, forcing chemists to conducta number of experiments in a short period of time [45].Also, the microwave technique is used in the foodindustry as well as in the pyrolysis of waste materials[46], the preparation of samples for analysis [47],extraction of natural products [48] and hydrolysis ofproteins and peptides [49].Microwave synthesis is among methods that respect the principles of the so-called “green chemistry”which is one more reason for performing this type ofsynthesis [50].In this paper, the synthesis of the certain 2-pyridones and 2-pyridone based compounds using micro-2wave irradiation will be discussed. We will point outthe advantages of microwave assisted synthesis in comparison to conventional heating. First, we will discussthe microwave synthesis of 2-pyridones. In the secondpart, microwave assisted synthesis of 2-quionoloneswill be given. At the end of the review, examples ofmicrowave synthesis of ring fused N-substituted 2-pyridones will be discussed.MICROWAVE SYNTHESIS OF 2-PYRIDONEThe application of microwave techniques in thesynthesis of organic compounds has inevitably led tothe microwave synthesis of compounds with the 2-pyridone ring. In the beginning, the synthesis was performed using conventional microwave ovens. Due tothe problems associated with the use of these ovens inthe synthesis (reproducibility, controllability and safety),dedicated microwave reactors were introduced. Thebasic principles of synthesis of heterocyclic moleculesused in conventional synthesis were applied to microwave synthesis [51]. Thus conducted synthetic routeyield pyridone ring from fragments containing differentnumbers of carbon atoms. Different combinations offragments were used: 4-1, 3-2, 1-3-1, 2-2-1 and 2-1-2.Condensation of type 4-1 means that the condensationinvolves two acyclic systems one of which has four andthe other only one carbon atom. Nitrogen can be a partof one of the fragments, or be introduced as a separatefragment.A good example of such a combination is given in apaper by Gorobets et al. [1], in which different carbonylbuilding blocks were reacted with N,N-dimethyl-

D.Ž. MIJIN et al.: MICROWAVE-ASSISTED SYNTHESIS OF 2-PYRIDONE-BASED COMPOUNDSHem. ind. 68 (1) 1–14 (2014)Conventional synthesis was performed by heating thereaction mixture under reflux (solvent mixture water//ethanol). Microwave synthesis was performed using aconventional microwave oven in the absence of solvent. The products were obtained in high yields and ina short reaction time (up to 7 min), while the conventional method of synthesis required up to 4 h with loweryields (Figure 4).6-Hydroxy-3-cyano-4-methyl-2-pyridone was alsosynthesized using microwave technique (condensationtype 3-2). The first microwave synthesis was reportedin 1994 in the German patent [52]. Compared to theconventional synthesis which takes 16.5 h with a yieldof 80%, microwave synthesis is carried out for 5 minwith a yield of 96%. In this synthesis, product wasobtained starting from cyanoacetamide, ethyl cyanoacetate and ethylamine. This pyridone can also beformamide dimethyl acetal (DMFDMA) to obtain enaminones in high yields (the reaction is carried out in theabsence of solvent and at elevated temperature). Theobtained enaminones, without purification, react withdifferent methylene nitriles at 100 C for 5 min in2-propanol and in the presence of a catalytic amount ofpiperidine (base). In this way, the authors were able toisolate 18 different 2-pyridones of 80 possible withyields varying from 27 to 96%, while some productswere obtained in pure form after simple filtration. Thissynthesis is given in Figure 2.An example of 3-2 type condensation of 3-cyano-2-pyridones is shown in Figure 3 [28]. N-substituted 4,6-dimethyl-3-cyano-2-pyridones were obtained fromacetylacetone and the corresponding N-substitutedcyanoacetamide using conventional and microwavesynthesis in the presence of piperidine as a catalyst.R2R1OODMFDMAR1N(CH3)2R2R1i-PrOH, piperidine, MWR3CH2CNN3RR2OFigure 2. Microwave synthesis of substituted 2-pyridones from enaminones.CH3H 3CNCO H 2CCNpiperidineCH2MW, 7 minOOH 3CNHRH 3CONRFigure 3. Synthesis of N-substituted 4,6-dimethyl-3-cyano-2-pyridones.1009080Yield (%)70605040302010Microwave H44-Cl-C6H4Ph4-MeO-C6H4BuPrEtMeH0Conventional synthesisFigure 4. N-Substituted 4,6-dimethyl-3-cyano-2-pyridones yields obtained by microwave and conventional synthesis.3

D.Ž. MIJIN et al.: MICROWAVE-ASSISTED SYNTHESIS OF 2-PYRIDONE-BASED COMPOUNDSobtained using conventional synthesis with potassiumhydroxide as a catalyst [27,53]. Reaction times variedfrom 1 to 8 h, with yields ranging from 40–60%.Recently, a synthesis of this pyridone was published,using microwave irradiation in a conventional microwave oven, in the absence of solvent starting fromethyl cyanoacetate and cyanoacetamide, using powdered potassium hydroxide as a catalyst (Figure 5). Theisolated yield was 60%, after only 4 min of irradiation[54].Dave et al. reported on microwave synthesis of 4,6-diaryl-3-cyano-2-pyridones starting from cyanoacetamide and 1,3-diarylpropen-1-ones in the presence ofpowdered potassium hydroxide, with phenyl or substituted phenyl groups in positions 4 and 6 [55]. Theauthors have reported yields that ranged from 74 to81% with high purity of compounds after only 1–2 minof irradiation (Figure 6).Microwave synthesis of arylazo pyridone dyes [56]is based on the previously described 3-2 type of condensation. This type of synthesis involves the reactionof phenylazo carbonyl compounds and cyanoacetamideusing KOH as base and ethanol as solvent in a dedicated microwave reactor. Synthesis of 5-phenylazo-4,6-dimethyl-3-cyano-2-pyridones and 5-phenylazo-4,6-diphenyl-3-cyano-2-pyridone are shown in Figure 7.Hem. ind. 68 (1) 1–14 (2014)The synthesized derivatives of 4,6-dimethyl-3-cyano-2-pyridone (Table 1, entries 1–6) were obtained in nearlyquantitative yield, while the derivatives of 4,6-diphenyl-3-cyano-2-pyridones (Table 1, entries 7–9) wereobtained in lower yields. Synthesis of 5-phenylazo-4,6-dimethyl-3-cyano-2-pyridone in the conventional manner [35] also takes place in the presence of a base inethanol, except that this synthesis lasted for 3 h withsomewhat lower yields (70–80%).Similarly, the synthesis of the 5-phenylazo-2-hydroxy-4-methyl-3-cyano-2-pyridones starting fromβ-phenylazo ketoesters under the same conditions wasperformed (Figure 7, Table 1, entries 10–13). In addition to these products a derivative of 2-hydroxy-4-phenyl-3-cyano-2-pyridones was also obtained (Table 1,entry 14). In comparison to derivatives of dialkyl 2-pyridone, lower yields were obtained as a result of lowerreactivity of β-keto esters compared to 1,3-diketones[56], in which is still higher yield compared to conventional synthesis (30–60%) [32].Synthesis of substituted 3-cyano-2-pyridones atpositions 4 and 6 was also carried out using microwaveirradiation (1-2-2 type condensation) [57], and underconventional conditions [58] (Figure 8). By applyingmicrowave irradiation (dedicated microwave reactor)yields of 90–95% over 5–7 min were obtained, whileH3CCH3ONCH2COCH2 OOMW, 4 minHONH2CH2CNKOHONHH3CFigure 5. Synthesis of H2NCOCH2CNMW, 1-2 minArNOHFigure 6. Synthesis of 4,6-diaryl-3-cyano-2-pyridones.R31R4O1N NRR2R5 'R3R O ONCR4EtOH, KOHMW, 130 oC, 5 min.NH2NR2R5Figure 7. Microwave synthesis of arylazo 4,6-dimethyl- and 4,6-diphenyl-3-cyano-2-pyridone dyes.4CNNNHO

D.Ž. MIJIN et al.: MICROWAVE-ASSISTED SYNTHESIS OF 2-PYRIDONE-BASED COMPOUNDSHem. ind. 68 (1) 1–14 (2014)Table 1. Synthesized arylazo 4,6-dimethyl- and 4,6-diphenyl-3-cyano-2-pyridone dyes with their MeMeMeMePhPhPhOHOHOHOHOHYield, CH3COONH3/EtOH/ΔCNHNAr CHO Ar COCH3ArNCCH2COOCH2CH3ArCH3COONH3/MW 5-7 minFigure 8. Conventional and microwave synthesis of substituted 3-cyano-2-pyridones.the conventional method of synthesis lasted for 6 h andgave lower yields (67–85%).Another example of microwave synthesis of 2-2-1condensing type of 2-pyridones is shown in Figure 9[59]. The synthesis of 3,5-dicyano-2-pyridone is carriedout in aqueous solution starting from aldehydes andmalononitrile in the presence of sodium hydroxide as abase. The advantage of this synthesis is short reactiontime, efficiency and use of water instead of organicsolvents which have a favorable impact on the environ-ment. The method is applicable not only to aromaticaldehydes with electron-donor and electron-acceptorgroups, but also to heterocyclic and aliphatic aldehydes.Syntheses were performed at 100 C both in theconventional and the microwave method. The reactiontime of microwave synthesis was 2–3 min while conventional synthesis took 2–3 h. On the other hand,reaction yields increased from 25–37% (conventional)to 40–49% (microwave synthesis).RNCRCHO 2 NCCH2CNCNNaOH, H2OMW, 100 oC, 2-3 minONNH2HFigure 9. Synthesis of 4-substituted 6-amino-3,5-dicyano-2-pyridones in aqueous media under microwave irradiation.5

D.Ž. MIJIN et al.: MICROWAVE-ASSISTED SYNTHESIS OF 2-PYRIDONE-BASED COMPOUNDS4-Aryl substituted 5-alkoxycarbonyl-6-methyl-3,4-dihydropyridones were prepared by the reaction ofMeldrum’s acid, methyl acetoacetate and appropriatebenzaldehyde in the presence of ammonium acetate(2-2-1 condensation type, Figure 10) [60–62]. Microwave assisted synthesis, performed in a dedicated microwave reactor, produced pure products in high yields(81–91%), while the conventional synthesis gave yieldslower by 17–28%.Synthesis of 2-pyridone based bifunctional compounds (1,4-dihydropyridines) by the condensation ofdialdehyde, Meldrum’s acid, acetoacetic acid andammonium acetate is another example of 2-2-1 typecondensation of pyridones (Figure 11) [63]. This synthesis was achieved by heating the reaction mixture ina conventional microwave oven for 8 min using smallHem. ind. 68 (1) 1–14 (2014)amounts of glycol as an energy transfer reagent (yield83%).MICROWAVE SYNTHESIS OF RING FUSED 2-PYRIDONEDERIVATIVESSynthesis of 2-quinolonesThe most widely used procedure for the synthesisof 2-quinolones is the reaction of aniline with malonicacid esters. However, this reaction is conducted at hightemperatures (250–350 C) that are difficult to achieveby conventional heating methods. The reaction of aniline with malonic acid esters produces two moles ofethanol, which affect the equilibrium between thereactants and the reaction products (Figure 12). ThereArOOCH3OCH3 COOCH3NH4OAcOOOCH3H3C ArCHOMWNOOCH3HFigure 10. Synthesis of 4-aryl substituted HOOHC NH4OAcOOOCH3COOCH2CH3H3COHH3CONHHNMW, 8 minCH3CH2OOCOCH3CH3OFigure 11. Synthesis of bifuncional 2-pyridone.OHR2R(EtOCO)CHR2NHR1RMW, 15 min, 500 WNOR1(EtOCO)CHR2- EtOHOORO- EtOHEtOHOEtNR1R22CRNORR1Figure 12. Formation of 3-substituted 4-hydroxy-2-quinolones in the reaction between anilines and substituted malonic esters.6

D.Ž. MIJIN et al.: MICROWAVE-ASSISTED SYNTHESIS OF 2-PYRIDONE-BASED COMPOUNDSmalonic acid can be used. Microwave synthesis of2-quinolones can be achieved in a conventional microwave oven by irradiation of a mixture of aniline andmalonic acid in the presence of dimethylformamide for3–5 min (yield 85–94%) [68].Instead of diethyl malonate/malonic acid, acetoacetic ester can be used. In this manner, carbostyrilanalogues can be synthesized (Figure 14). The synthesisis favored by electron-donor groups in the aniline ringand electron-acceptor groups in electrophilic compounds [69]. Microwave synthesis reduces the reactiontime from 18–58 h to just 80 min giving products ofhigh purity and in higher yield (58%).In a similar way, 2-quinolones can be obtained fromo-aminoarylketones and acetoacetic ester using microwave synthesis (4–6 min at 160 C in the presence of acatalyst (CeCl3 7H2O) – yields 85–95%) (Figure 15) [70].In comparison to conventional synthesis, microwavereactor synthesis shows that the reaction is 5 or moretimes faster using microwave technique.2-Quinolones can also be obtained by intramolecular Heck cyclizations of heteroarylamide [71]. Conventionally Heck cyclizations are achieved with N,N-dimethylacetamide (DMA) as a solvent, potassiumacetate and Pd(PPh3)4 as a catalyst at 120 C for 24 hwith yields from 56 to 89%. Microwave irradiationoften has a positive effect on the metal-catalyzed reactions [72–75] and in this case 2-quinolones werefore, it is essential, if the reaction is carried out in aclosed reactor, to maintain the volume and concentration of reactants low, in order to shift the equilibrium towards the products. On the other hand, thereaction can be carried out in an open vessel even on alarger scale without such demands [64]. It was foundthat the synthesis of 4-hydroxy-2-quinolones proceedsbest when an electron-donor group (R) is substituent inaniline. The nucleophilicity of the nitrogen is increasedand therefore both reactions, the condensation withthe malonic ester and the ring closing acylation proceed faster (Figure 5). The presence of R2-aryl groupprovides additional conjugation and stability of the product, which is reflected in the high product yield (up to94%) [64].This method cannot be applied in cases where anelectron-acceptor group (e.g., trifluoromethyl group) issubstituent in aniline. In this case, malondianilide wastreated with Eaton's reagent (7.7% phosphorus pentoxide in methanesulfonic acid) and resulted in highyield products (80–90%, Figure 13) [65,66].In addition to Eaton’s reagent, p-toluenesulfonicacid can be used in the microwave synthesis of 2-quinolones. 2-Qu

the advantages of microwave assisted synthesis in com-parison to conventional heating. First, we will discuss the microwave synthesis of 2-pyridones. In the second part, microwave assisted synthesis of 2-quionolones will be given. At the end of the review, examples of microwave synthesis of ring fused N-substituted 2-pyri-dones will be discussed.

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