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By Mehran Ali Use of Dimedone to Avail Various Novel Aminomethylene Compounds By Mehran Ali Department of Chemistry The Islamia University of Bahawalpur Session 2012-2014 i iii CONTENTS Page No. CHAPTER 1: SUMMARY x Chapter 1 2 INTRODUCTION 2 1.1 Dimedone 2 1.2 Physical properties of Dimedone 2 1.3 Tautomeric forms of Dimedone 3 1.4 Hydrogen bonding 3 1.5 Dimedone-Synthesis 3 1.6 Some important Reactions of Dimedone 4 1.6.1 Hantzsch reaction 4 1.6.2 Tandem Aldol-Michael reactions 4 1.6.3 Unsymmetrical Hantzsch reaction 5 1.6.4 One-pot Knoevenagel and Michael addition reaction: 5 1.6.5 Biuret reaction 6 1.6.6 Begenilli reaction 6 1.7 Importance of Dimedone 7 1.7.1 Pharmaceutical applications 7 1.7.2 In flavours and fragrance 8 1.7.3 In Laser dye and Photoinitiator 9 1.7.4 Dimedone as a probe 9 1.7.5 Dimedone as a trapper 10 1.8 Medicinal importance 10 1.8.1 Antibacterial activity 12 1.8.2 Anticonvulsant activity 12 1.8.3 Antimicrobial activity 13 1.8.4 Antioxidant properties 13 1.8.5 Antituberculosis activity 15 1.8.6 Cardiovascular activity 16 1.9 Biological importance 16 viii Chapter 2 20 LITERATURE REVIEW 20 AIM OF PROJECT 40 Chapter 3 42 EXPERIMENTAL 42 3.1 Solvents and Reagents 42 3.2 Solvents 42 3.3 Melting Point 43 3.4 Spectroscopy 43 3.5 Chromatography 43 3.6 General Method for the production of various novel C-2 substituted dimedones 44 3.7 Data of Synthesized Compounds 45 Chapter 4 56 RESULT AND DISCUSSION 56 4.1 1HNMR 59 4.2 13CNMR 59 REFERENCES 66 ix 1 Chapter 1 INTRODUCTION 1.1 Dimedone Dimedone (1) or Methone or 5,5-dimethyl-1,3-cyclohexanedione [1] is a highly reactive organic compound that is widely used in medicinal chemistry and organic synthesis. It is used as an active methylene compound as its most reactive centre i.e. C-2 is present between two strong electron withdrawing carbonyl groups. The C-2 of dimedone acts as a nucleophilic centre [2] while other less reactive sites i.e.C-1 and C-3 act as electrophilic centres. It is used in various organic reactions like knoevenagel condensation [3], Hantzsch reaction [4], Michael addition [3], Suzuki coupling [5] and Biginelli reaction [6] to form a number of useful products. It is also used as a precursor to form various biologically and pharmacologically active compounds that are used as anti-tumor [7], antibacterial [8], anti malarial [9], antifungal [10], antimicrobial [11] and antioxidant [12]. CH H3C 3 5 4 6 3 1 2 O O (1) 1.2 Physical properties of Dimedone The physical parameters of dimedone (1) are given in the table as under. Sr. No. Property State value 1 Molecular formula C8H12O2 [1] 2 Molecular mass 140.18[1] 3 Physical state Crystalline powder 4 Color Light yellow 5 Odor odorless 6 Decomposition point 147-150°C 7 Crystal structure Monoclinic[13] 2 1.3 Tautomeric forms of Dimedone In solution form, dimedone (1) exists in two tautomeric forms i.e. enol (2) and keto (1) in (1:2) ratio in chloroform [14]. O OH CH CH3 3 O O CH CH3 (1) 3 (2) 1.4 Hydrogen bonding Dimedone (1) in its crystalline form, exists in polymeric (3) forms of enol linked by hydrogen bonding [1]. H- - - - O O H3C CH3 H3C CH3 O- - - - O H (3) 1.5 Dimedone-Synthesis Dimedone (1) was prepared by the reaction of malonic ester (4) and mesityl oxide (5) [15]. ONa EtOOC CH3 O EtOOC EtOH COOEt + H C CH NaOEt 3 3 H3C O (4) (5) H3C O OH KOH H3C H C O HCl 3 OH CH3 CH3 (1) (Scheme 1) 3 An unpredicted formation of dimedone (1) was described by Henshall et al. [16] by the hydrolysis of 6-hydro-3-cyano-2-keto-4,4,6-trimethylpiperidine (6) in the presence of aqueous acetic acid and sulphuric acid. H3C CH3 H3C CH3 CN H2SO4(aq) COOH H3C -H2O H3C CH3COOH(aq) N O H3C COOH HO H O O (7) (6) (1) (Scheme 2) 1.6 Some important Reactions of Dimedone Dimedone is a well known organic molecule as it is an important part of almost every famous organic reaction and some of them are given as under. 1.6.1 Hantzsch reaction Wang et al. [4] has reported a synthetic strategy for polyhydroquinoline derivatives (9) by a simple multi component coupling reaction of dimedone (1), aldehydes and ethyl acetate (8) in the presence of ammonium acetate via Hantzsch mechanism. The reaction was aided by a small amount of Yb(OTf)3 (5 mol %) as a catalyst. The beneficial aspects of this strategy include eco friendly conditions, simple handling, normal temperature and high yield of the product. O O R O O Yb(OTf)3,5 mol 5% CO2Et 1eq. NH OAc H C 4 CH3 + H R + 3 O EtOH, r.t , 2-8 H, reflux H C N CH CH CO2Et 3 3 3 H3C H (1) (8) (9) (Scheme 3) 1.6.2 Tandem Aldol-Michael reactions Barakat et al. [17] has demonstrated a facile synthesis of some novel zwitter ion derivatives (12) by a one pot three components condensation reaction of dimedone (1), aldehydes (11) and various barbituric acid derivatives (10) using diethylamine under aqueous media via Tendem Aldol Michael mechanism. The charming aspects of this reaction were eco friendly conditions, less reaction time, high yield of the desired 4 product, simple workup, easy handling and affordable conditions. The structure of the synthesized compounds was verified by using various identification techniques such as, IR, NMR, Mass Spectroscopy, CHN, elemental analysis and X-ray diffraction. 1 R O H H3C O O O N O O H3C 1 1 R R H2O,NHEt2 N 1 + N N + R CH R.T,Reflux - + 3 HO O O NH2Et2 CH3 O O (1) (10) (11) (12) 2 R 2 R (Scheme 4) 1.6.3 Unsymmetrical Hantzsch reaction Davoodina et al. [18] has described an environmentally benign mechanism for the synthesis of polyhydroquinolines (14) via a multi component unsymmetrical Hantzsch reaction. The reaction underwent by condensing dimedone (1) with ammonium acetate, aldehydes and ethyl acetoacetate (13) in the presence of small amount of tet‐rabutylammonium hexatungstate [TBA]2[W6O19] as a catalyst in solvent free environment. The present protocol has been associated with plenty of benefits like, high activity and reusability of the catalyst and high yield of the product formed. O O R O O O CH3 [TBA]2[W6O19] OEt CH 3 R H + + NH4OAc O + EtO O Solvent free H3C N CH3 CH3 o 110 C H3C H (1) (13) (14) R= C6H5, 4-BrC6H4, 2-ClC6H4, 4-ClC6H4, 3-HOC6H4, 4-HOC6H4, 4-MeOC6H4, 4-MeC6H4 3-O2NC6H4 4-O2NC6H4 , 2-Furl, Et , n-Pr. (Scheme 5) 1.6.4 One-pot Knoevenagel and Michael addition reaction: Kantevari et al. [19] described a method for the production of 9-aryl-1,8- dioxooctahydroxanthene (15) derivatives and 2-aryl-methylene bis(3-hydroxy-2- cyclohexene-1-one) (16) derivatives through a Knoevenagel and Michael addition type 5 mechanism. The reaction proceeded by reacting dimedone (1) with various kinds of aldehydes under solvent free environment, aqueous media or using acetonitrile ,utilizing catalytic amounts of Silica supported perchloric acid ( HClO4–SiO2) and PPA–SiO2. O O O Ar O O Ar CH3 H O H3C CH Knoevenegal CH CH3 3+ ArCHO H C 3 O 3 O condensation Michael addition H3C OH CH (1) CH3 O 3 H3C HClO -SiO PPA-SiO2 4 2 O Ar O O Ar O O Ar O -H O 2 CH CH3 3 H3C H3C H3C O CH3 CH H3C CH3 O 3 H3C + H C OH OH (15) OH H CH3 3 (16) Ar = C6H5 , 4-ClC6H4 , 4-NMe2C6H4 , 3,4,5-(OMe)3C6H2, 4-OMe C6H4, 4-BrC6H4 , 3-OMe C6H4 , 4-NO2C6H4 , 2-NO2C6H4 , 4-OH C6H4, 3-Cl C6H4 , 2,4-Cl2C6H4 , 3-OH C6H4 , 4-CH3C6H4 (Scheme 6) 1.6.5 Biuret reaction Chassaing et al. [20] has described the formation of some unexpected products (18) by reacting different more or less active positions of dimedone (1) with benzofuroxan (17) in the presence of triethylamine. H CH3 CH3 OH O O N N O Et3N CH3 + O N O N CH 3 O CH3 H3C (1) (17) (18) (Scheme 7) 1.6.6 Begenilli reaction Chebanov et al. [6] presented a sonication assisted synthesis of some novel pyrazoloquinazolinone derivatives (20) by a Begenelli type coupling mechanism. The 6 reaction was done by refluxing dimedone (1) with various aromatic aldehydes and phenylpyrazol derivatives (19) for 30 minutes using ethanol as solvent. O N NH Ar O O N NH2 Sonication,EtOH N CH 3 H Ar + O + CH3 Reflux, 30 mins N CH3 H H C (1) (19) (20) 3 Ar = C6H5 , 4-MeC6H4 , 4-MeOC6H4, 4-BrC6H4, 4-NO2C6H4 , 2-MeOC6H4 (Scheme 8) 1.7 Importance of Dimedone Dimedone (1) is a valuable compound that has vast applications in biological and pharmaceutical field respectively and is used in a variety of purposes as under. 1.7.1 Pharmaceutical applications Dimedone (1) has been utilized in the preparation of substituted quinolines (21) [21] by a regioselective one pot two component method from formylated acetophenone and dimedone assisted by potassium bisulphate in aqueous media. Such type of compounds having quinoline groups show intense biological activities including anti asthmatic, anti infalammatory, anti hypertensiv and tyrosine kinase inhibiting agent.
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