SYNTHESIS AND CHARACTERIZATION OF PYRROLE 2, 5-DIONE DERIVATIVES

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1 SYNTHESIS AND CHARACTERIZATION OF PYRROLE 2, 5-DIONE DERIVATIVES *Shipra Baluja, Kajal Nandha and Paras Ramavat Department of Chemistry, Physical Chemical Laboratory, Saurashtra University, Rajkot (Gujarat), India *Author for Correspondence ABSTRACT Some new Pyrrole 2, 5-dione derivatives were synthesized by condensation of 2-hydrazinyl-2-oxo-Nphenylacetamide and maleic anhydride. The characterization of these synthesized compounds was done by IR, 1 H NMR and mass spectral analysis. Keywords: Pyrrole 2, 5-Dione Derivatives INTRODUCTION Pyrrole is an important class of heterocyclic compounds which are widely known as biologically active scaffold due to its diverse nature of activities. The combination of different pharmacophores in a pyrrole ring system has led to the formation of more active compounds. The pyrrole ring is present in many natural products such as alkaloids, bile pigments and other natural products such as porphyrins, chlorophyll (vitamin B 12) etc (Mohamed and Fathallah, 2014). Many drugs such as bepridil and procyclidine also contain pyrrole moiety (Shorvon, 2001). Substitution at nitrogen of pyrrole ring has proved the enhancement of biological activities of pyrrole nucleus. Some of these biological activities are antiviral (Jigarkumar et al., 2014), CNS depressant (Malinka et al., 2000), antibacterial (Seref et al., 1999), antitumor (Maria et al., 2003), anticonvulsant (Sorokina et al., 1989) and anti HIV (Shibo et al., 2004) etc. Patil et al., (2009) have reported the anticonvulsant activities of N- substituted 2, 5-dimethyl pyrrole and bipyrrole. The anti-inflammatory activity of some new succinic and maleic derivatives was reported by Chien et al., (2008). The antimalarial and antimicrobial activity of some new pyrrolone derivatives have also been reported by some workers (Dinakaran et al., 2013). Guiqing et al., (2014) have studied the antitumor activity of pyrrole analogs against cancer cell lines. In present paper, some new Pyrrole 2, 5-dione derivatives have been synthesized and characterization of these synthesized compounds was done by IR, 1 H NMR and mass spectral data. MATERIALS AND METHODS Synthesis of ethyl 2-oxo-2-(phenylamino) acetate derivatives: Equimolar solution of different substituted amine and diethyl oxalate in 1, 4-dioxane was refluxed for 5-6 hrs. The completion of reaction was confirmed by analytical thin layer chromatography (TLC) (Performed on aluminum coated plates Gel 60F 254 (E. Merck)) using (0.7: 0.3-Hexane: Ethyl acetate) as mobile phase. After completion of reaction, the reaction mass was cooled and the resulting solid was poured into crushed ice and was washed with acidic water to remove unreacted amine. The solid was then filtered and dried under vacuum. Copyright 2014 Centre for Info Bio Technology (CIBTech) 61

2 Synthesis of 2-hydrazinyl-2-oxo-N-phenylacetamide derivatives: A methanolic solution of ethyl 2- oxo-2-(phenylamino) acetate and hydrazine hydrate was stirred at C for 30 minutes. The progress of reaction was monitored by thin layer chromatography using (0.5:0.5-Hexane: Ethyl acetate) as mobile phase. The solid was filtered, washed with methanol and dried. Synthesis of N 1 -(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N 2 -phenyloxalamide derivatives: Equimolar solution of 2-hydrazinyl-2-oxo-N-phenylacetamide and maleic anhydride in glacial acetic acid was refluxed for 2-3 hrs. The progress of reaction was monitored by TLC using (0.6:0.4-Hexane: Ethyl acetate) as mobile phase. After completion of reaction, the reaction mass was poured into crushed ice. The solid was filtered, washed with water and dried under vacuum. Overall, ten derivatives were synthesized, which are as follows: RPA-1: N 1 -(3-chloro-4-fluoro phenyl)-n 2 -(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl) oxalamide RPA-2: N 1 -(4-bromophenyl)-N 2 -(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)oxalamide RPA-3: N 1 -(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N 2 -(3-nitrophenyl)oxalamide RPA-4: N 1 -(2,5-dimethylphenyl)-N 2 -(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)oxalamide RPA-5: N 1 -(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N 2 -(4-fluorophenyl)oxalamide RPA-6: N 1 -(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N 2 -(2-methoxyphenyl)oxalamide RPA-7: N 1 -(3,4-dichlorophenyl)-N 2 -(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)oxalamide RPA-8: N 1 -(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N 2 -(pyridin-4-yl)oxalamide RPA-9: N 1 -(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N 2 -(3-methoxyphenyl)oxalamide RPA-10: N 1 -(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N 2 -(4-nitrophenyl)oxalamide All the synthesized compounds were recrystallized using THF. The structure confirmation of these crystallized compounds was done by FTIR, 1 H NMR and mass spectral data. IR spectra were recorded on IRaffinity 1S (furrier transport infra-red spectroscopy). 1 H- NMR spectra were taken on a Bruker AVANCE II 400. In all the cases, 1 H NMR spectra were obtained in DMSO-d 6 using TMS as an internal standard. The NMR signals are reported in δ ppm. The mass spectra were determined using direct inlet probe on a GCMS-QP-2010 mass spectrometer. Figures 1 to 3 show the IR, 1 H NMR and mass spectrum of some compounds. Copyright 2014 Centre for Info Bio Technology (CIBTech) 62

3 The melting points of compounds were measured by Differential Scanning Calorimeter (DSC) (Model- Shimadzu-DSC-60). Table 1 shows physical properties of all the synthesized compounds. Table 1: Physical constants of pyrrole-2, 5-dione derivatives Compound Code Substitution R M.F. M.W. Yield (%) RPA-1-3-Cl, 4-F C 12H 7ClFN 3O RPA-2-4-Br C 12H 8BrN 3O RPA-3-3-NO 2 C 12H 8N 4O RPA-4-2,5-di-CH 3 C 14H 13N 3O RPA-5-4-F C 12H 8FN 3O RPA-6-2-OCH 3 C 13H 11N 3O RPA-7-3,4-di-Cl C 12H 7Cl 2N 3O RPA-8 -C 5H 4N C 11H 8Cl 2N 4O RPA-9-3-OCH 3 C 13H 11N 3O RPA-10-4-NO 2 C 12H 8N 4O *0.6:0.4 - Hexane: Ethyl acetate R f* value Figure 1: IR spectrum of compound RPA-1 Copyright 2014 Centre for Info Bio Technology (CIBTech) 63

4 Figure 2: 1 H NMR spectrum of compound RPA-1 Figure 3: Mass spectrum of compound RPA-1 Spectral Data RPA-1 IR: (-NH str.), (Ar-CH str.), (carbonyl str.), (N-H bend.), (Ar- C=C- str.), (Ar-C-C str.), (-C-H rock), (-C-N str.), (Ar-C-H bend.), (-C-H oop ). 1 H NMR (DMSO-d6) δ(ppm): (2H, singlet, -CH of pyrrole ring), (2H, mulltiplet, Ar-CH), (1H, singlet, Ar-CH), (1H, singlet, -NH-N), (1H, singlet, -NH-Ar). MS: (m/z) = 311 Copyright 2014 Centre for Info Bio Technology (CIBTech) 64

5 RPA-2 IR: (-NH str.), (Ar-CH str.), (carbonyl str.), (N-H bend.), (Ar- C=C- str.), (Ar-C-C str.), (-C-H rock), (-C-N str.), (Ar-C-H bend.), (-C-H oop ). 1 H NMR (DMSO-d6) δ(ppm): (2H, singlet, -CH of pyrrole ring), (2H, doublet, Ar-CH), (2H, doublet, Ar-CH), (1H, singlet, -NH-N), (1H, singlet, -NH-Ar). MS: (m/z) = 338 RPA- 3 IR: (-NH str.), (Ar-CH str.), (carbonyl str.), (N-H bend.), (Ar- C=C- str.), (Ar-C-C str.), (-C-H rock), (-C-N str.), (Ar-C-H bend.), (-C-H oop ). 1H NMR (DMSO-d6) δ(ppm): (2H, singlet, -CH of pyrrole ring), (1H, mulltiplet, Ar-CH), (2H, doublet, Ar-CH), (1H, singlet, Ar-CH), (1H, singlet, - NH-N), (1H, singlet, -NH-Ar). MS: (m/z) = 304 RPA-4 IR: (-NH str.), (Ar-CH str.), (-CO- str.), (N-H bend.), (Ar- C=C- str.), (Ar-C-C str.), (-C-H rock), (-C-N str.), (Ar-C-H bend.), (-C-H oop ). 1 H NMR (DMSO-d 6) δ(ppm): (6H, single, -CH 3 of), (2H, singlet, -CH of pyrrole ring), (1H, doublet, Ar-CH), 7.513(1H, doublet, Ar-CH), (1H, singlet, Ar-CH), (1H, singlet, -NH-N), (1H, singlet, -NH-Ar). MS: (m/z) = 287 RPA-5 IR: (-NH str.), (Ar-CH str.), (carbonyl str.), (N-H bend.), (Ar- C=C- str.), (Ar-C-C str.), (-C-H rock), (-C-N str.), (Ar-C-H bend.), (-C-H oop ). 1 H NMR (DMSO-d6) δ(ppm): (2H, singlet, -CH of pyrrole ring), (2H, mulltiplet, Ar-CH), (2H, doublet, Ar-CH), (1H, singlet, -NH-N), (1H, singlet, -NH-Ar). MS: (m/z) = 277 RPA-6 IR: (-NH str.), (Ar-CH str.), (carbonyl str.), (N-H bend.), (Ar- C=C- str.), (Ar-C-C str.), (-C-H rock), (-C-N str.), (Ar-C-H bend.), (-C-H oop ). 1 H NMR (DMSO-d6) δ(ppm): (1H, singlet, -OCH 3), (2H, singlet, -CH of pyrrole ring), (2H, doublet, Ar-CH), (1H, singlet, Ar-CH), (1H, singlet, - NH-N), (1H, singlet, -NH-Ar). MS: (m/z) = 289 RPA-7 IR: (-NH str.), (Ar-CH str.), (carbonyl str.), (N-H bend.), (Ar- C=C- str.), (Ar-C-C str.), (-C-H rock), (-C-N str.), (Ar-C-H bend.), (-C-H oop ). 1 H NMR (DMSO-d6) δ(ppm): (2H, singlet, -CH of pyrrole ring), (2H, doublet, Ar-CH), (1H, singlet, Ar-CH), (1H, singlet, -NH-N), (1H, singlet, -NH-Ar). MS: (m/z) = 326 RPA-8 IR: (-NH str.), (Ar-CH str.), (carbonyl str.), (N-H bend.), (Ar- C=C- str.), (Ar-C-C str.), (-C-H rock), (-C-N str.), (Ar-C-H bend.), (-C-H oop ). 1 H NMR (DMSO-d6) δ(ppm): (2H, singlet, -CH of pyrrole ring), (2H, doublet, Ar-CH), (2H, doublet, Ar-CH), (1H, singlet, -NH-N), (1H, singlet, -NH-Ar). MS: (m/z) = 260 RPA-9 IR: (-NH str.), (Ar-CH str.), (carbonyl str.), (N-H bend.), (Ar- C=C- str.), (Ar-C-C str.), (-C-H rock), (-C-N str.), (Ar-C-H bend.), (-C-H oop ). 1 H NMR (DMSO-d6) δ(ppm): (1H, singlet, -OCH 3), (2H, singlet, -CH of pyrrole ring), (2H, doublet, Ar-CH), (1H, singlet, Ar-CH), (2H, multiplet, Ar-CH), (1H, singlet, -NH-N), (1H, singlet, -NH-Ar). MS: (m/z) = 289 Copyright 2014 Centre for Info Bio Technology (CIBTech) 65

6 RPA-10 IR: (-NH str.), (Ar-CH str.), (carbonyl str.), (N-H bend.), (Ar- C=C- str.), (Ar-C-C str.), (-C-H rock), (-C-N str.), (Ar-C-H bend.), (-C-H oop ). 1 H NMR (DMSO-d6) δ(ppm): (2H, singlet, -CH of pyrrole ring), (2H, doublet, Ar-CH), (2H, doublet, Ar-CH), (1H, singlet, -NH-N), (1H, singlet, -NH-Ar). MS: (m/z) = 304 CONCLUSION Overall ten compounds were synthesized and structure confirmation was done by IR, 1 H NMR and mass spectral analysis. REFERENCES Carson JR, Carmosin RJ, Pitis PM, Vaught JL, Almond HR, Stables JP, Wolf HH, Swinyard EA and White HS (1997). Aroyl (aminoacyl) pyrroles, a new class of anticonvulsant agents. Journal of Medicinal Chemistry Chien S, Chen M, Kuo H, Tsai Y, Lin B and Kuo Y (2008). Anti-inflammatory activities of new succinic and maleic derivatives from the fruiting body of antrodia camphorate. Journal of Agricultural and Food Chemistry Dinakaran M, Kaiser M, White KL, Norval S, Riley J, Wyatt PG, Charman SA, Read KD, Yeates C and Gilbert IH (2013). Structure-activity relationship studies of pyrrolone antimalarial agents. ChemMedChem Guiqing X, Duanyang K, Wei L, Wenjing X and Jiang Y (2014). Synthesis of maleimide derivatives via CuAAC click chemistry and biological evaluation of their antitumor activity against cancer cell lines. Journal of Chemical and Pharmaceutical Research Jigarkumar P, Malani M, Andrei G, Balzarini J, Snoeck R and Dholakiya B (2014). An Efficient synthesis and antiviral activity evaluation of 1-(4-(5-Phenyl-4, 5 dihydro-1h-pyrazole (& (4, 5 dihydroisoxazole))-3-yl)-phenyl)-pyrrole-2, 5-dione derivates. Anti-Infective Agents Malinka W, Dziuba MS, Rajtar G, Rejdak R, Rejdak K and Kleinrok Z (2000). Synthesis of some N-substituted 3,4-pyrroledicarboximides as potential CNS depressive agents. Pharmazie Maria TC, Cenzo C and Valentina O (2003). Synthesis and in vitro antitumoral activity of new N- phenyl-3-pyrrolecarbothioamides. Bioorganic & Medicinal Chemistry Marta S, Krawiecka M, Kossakowski J, Stefanska J, Miroslaw B and Koziol AE (2008). Synthesis and structural characterisation of derivatives of tricyclo( ,6 )dec-8-ene-3,5-dione with an expected antimicrobial activity. Journal of the Chinese Chemical Society Mohamed MS and Fathallah SS (2014). Pyrroles and fused pyrroles: synthesis and therapeutic activities, Mini-Reviews in Organic Chemistry Patil VM, Sinha R, Masand N and Jain J (2009). Synthesis and anticonvulsant activities of small n- substituted 2, 5-dimethyl pyrrole and bipyrrole. Digest Journal of Nanomaterials and Biostructures Seref D, Ahmet CK and Nuri K (1999). Synthesis and antibacterial activities of some 1-(2-(substituted pyrrol-1-yl)ethyl)-2-methyl-5-nitroimidazole derivatives. European Journal of Medicinal Chemistry Shibo J, Hong L, Shuwen L, Qian Z, Yuxian H and Asim K (2004). N-substituted pyrrole derivatives as novel human immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six-helix bundle formation and block virus fusion. Antimicrobial Agents and Chemotherapy Shorvon S (2001). Pyrrolidone derivatives. Lancet Sorokina IK, Andreeva NI and Golovina SM (1989). Synthesis and anticonvulsant activity of 3- dimethylaminomethyl-8-oxoindeno-(2,1-b)pyrroles. Pharmaceutical Chemistry Journal Copyright 2014 Centre for Info Bio Technology (CIBTech) 66