Polyethylene glycol(PEG-400): An efficient and recyclable reaction medium for the synthesis of novel

Available online at www.sciencedirect.comCHINES E。ScienceDirectC HEMICALL ETTERSELSEVIERChinese Chemical Letters 22 (2011) 65-68www.elsevier.com/locate/ccletPolyethylene glycol (PEG-400): An eficient and recyclablereaction medium for the synthesis of novel 1, 5-benzodiazepinesand their antimicrobial activityShankaraiah G. Konda, Baseer M. Shaikh, Sanjay A. Chavan, Bhaskar S. Dawane *Organic Research Laboratory, Department of Chemistry Yeshwant Mahavidyalaya, Nanded-431602 (M.S) IndiaReceived 20 May 2010AbstractA new series of imidazole containing I, 5-benzodiazepines have been synthesized by the condensation of chalcones with 0-phenylenediamine using piperidine in polyethylene glycol (PEG-400) as an eficient and green reaction solvent. The advantages ofthis protocol are environmental friendliness, easy work-up, high yields. mild reaction condition and avoidance of expensive catalyst.Furthermore, newly synthesized compounds were evaluated for their antimicrobial activity.C 2010 Bhaskar S. Dawane. Published by EIsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.Keywonds: PEG 400; Chalcones; o-Phenylenediamine; I; 5-Benzodiazepines; Antimicrobial activityBenzodiazepines have attracted attention as an important class of heterocyclic compounds in the field of drugs andpharmaceuticals. These compounds are widely used as anticonvulsant, antianxiety, analgesic, sedative, anti-depressive, antibacterial, hypnotic agents as well as anti-infammatory agents [1]. Moreover, I, 5-benzodiazepines arealso useful precursors for the preparation of other fused ring compounds such as triazolo-, oxadiazolo-, oxazino-, orfuranobenzodiazepines [2]. On the other hand, imidazole ring has wide applications in medicinal chemistry. It is alsoreported that, imidazole derivatives are gained synthetic interest in recent years due to their broad spectrum ofbiological properies [3,4].I, 5-Bnezodizepines were commonly synthesized by the reaction of o-phenylenediamine with a, B-unsaturatedcarbonyI compounds, B-haloketones. There are many methods in the literature for the preparation of I, 5-benzodiazepines such as BF;-etherate [5]. NaBH4 |6], SiO2 [7]. Amberlyst-15 |8]. Yb(0t)3 [9], MgO/POCl; [10],Al2O;/P2Os [11], CH;COOH in MWI, TiCl4/THF [12], [bbim] ionic liquid [13] silica-gel [14], CeCis/silica-gel [15].However, many of these procedures have one or more disadvantages such as use of expensive catalyst, long reactiontime, high catalyst loading, low selectivity, requirements of special apparatus, and side reaction. In recent yearsreplacement of hazardous-solvents with environmentally benign solvents is one of the major focus areas of greenchemistry. The utility of alternative reaction solvents such as water [16], ionic liquid [17], flourous [18|, supercriticalmedia [19] and polyethylene glycol (PEG) [20] is rapidly growing. Liquid polymers or low melting polymers have* Corresponding author.中国煤化工Email ddresses: kondasgerediffmail.com (S.G. Konda). bhaskardawane@rYHCNMHG1001-8417/5 - see front matter C 2010 Bhaskar S. Dawane. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.doi: 1016.celt.2010.09.0266S.G. Konda et al,/Chinese Chemical Letters 22 (2011) 65- 68CLNH2N.ArHPEG-400piperidineA1(a-)o-pbenylenediamine2(a-I)Scheme 1. Synthetic route for l,5-benzodizepines 2(a-).Table 1Physical-chemical data of 1, 5-benzodizepine derivatives.EntryProductTime (min)Yield (%)M. P.(°C)2a2-0H-5_CI-C6H435901262b4-CI-CHs2:941522-0H-3-iod0-5-CI-CcH33889134)d2-0H-3-bromo-5-CI-C&H3125le2-0H4-CH-5-CI-CH4401162f2-0H-3-iodo 4-CH3-5-CI-C&H44422g2-0H-3-bromo- 4CHg.5-CI-CH44C1202h2-0H-3-iodo-5-CH3-CH34S135212-0H-3-brom0-5-CHJ-CgH39102102-0H-3, 5-diiodoC&H11912k2-0H-3, 5-dibromo-C.H3161122-0H-3, 5-dichloro-CcH33(2115emerged as alternative green reaction media. Polyethylene glycol (PEG-400) prompted reactions [21- -24] haveattracted the atention of organic chemists due to their solvating ability and aptitude to act as a phase transfer catalyst,negligible vapor pressure, easy recyclability, ease of work-up, eco-friendly nature and economical cost. PEG is non-toxic, non-halogenated, inexpensive potentially recyclable and water soluble which facilitate its removal from reactionproduct.With our recent success on the development of new selective environmentally friendly methodologies usingpolyethylene glycol (PEG-400) [25- -27] as a solvent for the preparation of biologically active compounds, herein wereport the synthesis of some new 1,5-benzodiazepines by the reaction of chalcones with o-phenylenediamine usingpiperidine in PEG-400 as green reaction solvent (Scheme 1, Table 1). The starting materials (chalcones) were preparedby the reported method [25].Initill, we atempted the condensation 1-(4-chloropheny)-3-(2 -butyl-5-chloro-3H imidazol-4y)-2- propen-1-one with o-phenylenediamine using piperidine in polyethylene glycol (PEG 400) as reaction solvent. The reactionwent to completion within 25 min and corresponding product (2b) was obtained in 94% yield. In order to optimize thereaction conditions, we carried out the above reaction in different solvents such as ethanol, acetic acid, dioxane, DMFand polyethylene glycol-400 (Table 2). We found that polyethylene glycol-400 as an efficient reaction medium intermsof reaction time as well as yields (94%). Encouraged by the results, we turned our attention to variety of substitutedchalcones. In all cases, the reaction proceeded efficiently in high yields at 60。C using PEG- 400 as an alternativereaction solvent. These newly synthesized compounds were screened for their antimicrobial activity.Table 2Effect of solvent on the reaction of 1<4-choropeny)-3-(2 butyl-5-chloro-3H-imidazol-4y)-2 propen-1-one with o-phenylene diamine.SolventTime (h)EtOH中国煤化工6:CHzCOOHMHCNMHG7Dioxane6DMF525 (min)S.G. Konda et al./Chinese Chemical Letters 22 (2011) 65 -6867Table 3Antimicrobial activity of syntbesized 1, 5-benzodiazepines 2(a-1).ProductBacteriaFungiEcPvBsSaAnAfPc2a12114|2132t2152c01610532d20172e21411l02g182h2i2j62k7Penicili8IANANystainNZone of inhibition is expressed in mm; Ec- Escherichia coli, Pv- Proteus vulgaris, Bs- Bailus subillis, Sa- Staphylococcus aureus, An-Aspergilusniger, Af-Aspergillus favus, Pc-Penicillium cbrysogenum; - No activity, NA-Not Applicable.The antimicrobial activities of the synthesized compounds 2(a-1) were determined by agar well diffusion method[28]. The results of antimicrobial data are given in Table 3. In comparison with the standard antibacterial agent,compounds 2d, 2 g and 21 are active against E. coli. Compounds 2c, 2 h, 2j and 2k were showed comparative activityagainst P. vulgaris. Moreover, 2d, 2i, 2k and 21 were relatively active against s. aureus. Only the compounds 2d and 2jwere displayed very good activity against B. subilis. On the other hand, the compounds 2c and 2j showed goodantifungal activity whereas 2k and 21 showed similar level of activity againstA. niger. Compounds 2j, 2k and 21 werealso showed stronger activity against A. flavus. In comparison with standard antifungal agent, compounds 2d, 2 g and2j displayed a very good activity against P. chrysogenum.When structure activity relationships are investigated, the antimicrobial activity might be increased by thesubstitution of hydroxyl group in Cz-position and presence of halo (I, Br and Cl) groups as substituents at C3 and Csposition on the benzene nucleus. Furthermore, compounds bearing methyl groups in combination with I and Br whichenhanced the activity.Typical procedure for the synthesis of l,5-benzodiazepines 2(a-I):A mixture of substituted chalcone 1 (1 mmol), o-phenylenediamine (1.5 mmol) and piperidine (1 mL) inpolyethylene glycol (PEG-400) (15 mL) was heated at 60°C for the period as shown in Table-1. After completion ofreaction (TLC), the reaction mixture was extracted with ethyl acetate (2 X 20 mL). The combined organic layers weredried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure. The obtained product wasrecrystallized by aqueous acetic acid to give pure product. PEG-400 was recovered and further used for next run.2,3-Dihydro-2-(2-hydroxy-5-chloropheny)- 4-(2-buryl-4-chloro-1H-imidazol-5-yl)-1H-1,5-benzodiazepine (2a):IR (KBr, cm-'): 1605, 3178, 3338; 'H NMR (DMSO-d6): 80.91 (, 3H, -CH3), 1.31 (m, 2H, -CH2-), 1.71 (m,2H, -CH2), 2.65 (t, 2H, -CH2), 3.22 (m, 2H), 3.51 (m, 1H), 4.31 (s, 1H), 7.08-8.15 (m, 8H, Ar-H), 10.92 (s, 1H, OH);M.S. (m/2): 428 M"); Anal. Calcd. for C22H22N4OC:; C, 61.54; H, 5.16; N, 13.05%. Found: C, 61.46; H, 5.21; N,13.11%2,3-Dihydro-2-(4 chlorophenyl)-4-(2-butyl 4 chloro-1H-imidazol-5-yl)-1H-l,5-benzodiazepine (2b): IR (KBr,cm^ ): 1601, 3312; 'H NMR (DMSO-d6): δ 0.89 (t, 3H, -CH3), 1.25 (m, 2H, -CH2), 1.71 (m, 2H, -CH2), 2.61(t, 2H, -CH2), 3.25 (m, 2H), 3.55 (m, 1H), 4.28 (s, lH), 7.05-7.98 (m, 9H, Ar-H); M.S. (m/2): 412 M*); Anal. Calcd.for C22H22N4Cl2: C, 63.93; H, 5.36; N, 13.55%. Found: C, 63.98中国煤化工1H-1,5-benzo-dia-2,3-Dihydro-2-(2-hydroxy-4-methyl-5-chlorophenyl)-4-(2-butyzepine (2e): IR (KBr, cm ): 1602, 3162, 3318; 'H NMR (DMSO-diYHC N M H Gm, 2H, -CH2-), 1.61(m, 2H, -CH2), 2.72 (t, 2H, -CH2), 3.21 (m, 2H), 3.55 (m, 1H), 4.34 (s, 1H), 7.18-8.21 (m, 7H, Ar-H), 10.89 (s, 1H,0H); M.S. (m/z): 442 (M); Anal. Calcd for C23H24N4OCl2: C, 62.31; H, 5.46; N, 12.64%. Found: C, 62.36; H, 5.52;N, 11.52%.68S.G. Konda et al. /Chinese Chemical Letters 22 (2011) 65-68In summary, we have developed a novel, efficient and environmentally benign methodology towards the synthesisof 1,5-benzodiazepines by the condensation reaction of chalcones with o-phenylenediamine using pipenidine inpolyethylene glycol (PEG-400) as an efficient and green reaction solvent is described. The advantages of the presentprotocol are the simplicity of operation, the high yields of products, the recyclability of PEG-400, avoidance ofexpensive catalyst and usage of volatile organic solvents. Antimicrobial data revealed that compounds carrying 2-hydroxy-3-iodo-5-chlorophenyI, 2-hydroxy-3-bromo 5-chlorophenyl, 2-hydroxy-3,5-diodopbenyI, 2-hydroxy-3,5-dibromophenyI and 2-hydroxy 3,5- dichlorophenyl were exhibited good antifungal and antibacterial activity.Therefore, the present study is more beneficial to the synthesis of new drugs with medicinal investigation againstbacterial and fungal diseasesAcknowledgmentsBSD gratefully acknowledge to UGC-New Delhi, for Post Doctoral research award and SGK is also thankfulUGC-New Delhi for D. S. Kothari Post Doctoral fellowship. The authors are grateful to the Director, IICT, Hyderabadfor providing necessary instrumental facilities.References[|] H. Schutz, Comprehensive Heterocyelic Chemistry 1 (1984) 116.[2] M.C. Aversa, A. Ferdazzo, P. Giannetto, et al. 1. Heteroeyel. Chem.27 (1990) 371.[3] D.H. Slee. SJ. Romano,J. Yu, et al. J. Med. Chem. 44 (2001) 2094.[4] S. Khabnadideh, z. Rezaci. A. Khalaf-Nezhad, et al. Bioorg. Med. Chem. 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