J. Serb. Chem. Soc. 70 (10) (2005) UDC

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1 J. Serb. Chem. Soc. 70 (10) (2005) UDC JSCS 3353 Short communication SHORT COMMUNICATION Green chemistry approach to the synthesis of potentially bioactive aminobenzylated Mannich bases through active hydrogen compounds S.L.VASOYA,P.T.CHOVATIA,D.H.PUROHITandH.S.JOSHI * Department of Chemistry, Saurashtra University, Rajkot , Gujarat, India ( -drhsjoshi@yahoo.com) (Received 22 July, revised 13 December 2004) Abstract: An efficient and high yield method for the synthesis of aminobenzylated Mannich bases is described. The synthesis occurs in aqueous medium at 0 ºC. The compounds show moderate antitubercular and antimicrobial activities. Keywords: aminobenzylated Mannich bases, antitubercular activity, antimicrobial activity. INTRODUCTION Compounds containing active hydrogen atoms yielded aminobenzylated Mannich bases with secondary amines and aromatic aldehydes. Mannich bases are important compounds owing to their wide range of biological and industrial applications. They are also employed as intermediates 1,2 in chemical synthesis and polymer chemistry. Several important therapeutic compounds have been synthesized via the Mannich reaction. 3 6 They have also been found to possess pharmacological activities, such as antihypertensive, 7 antipsychotic, 8 anaesthetic, 9 antitubercular, 10 etc. The starting 3-phenoxybenzaldehyde in reaction with cyclic secondary amines, such as piperidine, morpholine, indole and N-methylpiperazine, gives rise to intermediate N-cyclic phenyl carbinols, which on condensation with active hydrogen compounds, such as acetamide, urea and thiourea, yield Mannich bases (1 3) (Scheme 1). The structures of the synthesized compounds were assigned on the basis of elemental analyses, FTIR, 1 H-NMR and MS spectral data. The compounds were screened for their in vitro antitubercular and antimicrobial activity. EXPERIMENTAL Thin layer chromatography was used to monitor the reactions and the purity of the synthesized compounds. The melting points were determined in open capillary tubes and are uncorrected. The * Author for correspondence. doi: /JSC V 1163

2 1164 VASOYA et al. Scheme 1. IR spectra were recorded on a Shimadzu FTIR-8400 instrument using the KBr disc technique and only noteworthy absorptions (cm -1 ) are listed. The 1 H-NMR spectra were recorded on a Bruker AC-300 MHz FT-NMR using TMS as the internal standard (chemical shifts in value). From the structure activity relationship, it was found that compounds 1a, 1b, 2c, 3a, 3c and 3d show moderate antitubercular activity against Mycobacterium tuberculosis strain H 37 Rv. In the case of antimicrobial activity, compounds 1c, 2d, 3d were found to be active against E. coli, while1b, 3c showed moderate activity against P. vulgaris and compounds 2d, 1d and 3b were active against B-megaterium. Compounds 1a, 1b, 1d, 2b, 2c, 3a and 3b showed prominent activity against S. aureus. Preparation of N-(3-phenoxy- -piperidin-1-ylbenzyl)acetamide (1a) To an aqueous solution of acetamide (0.075 mol, 4.42 g), piperidine (0.05 mol, 4.25 g) was added and stirred to obtain clear solution. 3-Phenoxybenzaldehyde (0.05 mol, 9.9 g) was then added dropwise and the mixture was stirred for 2 h in an ice-bath. The resulting colloidal solution was kept at room temperature for about a week with occasional stirring. The precipitate was isolated by vacuum filtration and recrystallized from methanol. Compound 1a: yield 75 %, m.p. 135 ºC. Anal. Calcd. for C 20 H 24 N 2 O 2 : C, 74.07; H, 7.40; N, 8.64 %; Found: C, 74.05, H, 7.37, N, 8.62 %. IR

3 SYNTHESIS OF BIOACTIVE MANNICH BASES 1165 (KBr) max 1693 (C=O), 3050 ( NH) cm -1.NMR 2.12 (3H, s, CH 3 ), 9.96 (1H, s, NH), (10H, m, Ar H). The mass spectrum indicated the molecular ion peak at m/z 324. The reaction procedure leading to 1a was then extended to the syntheses of 1b 1d. The physical data of the obtained compounds are listed in Table I. TABLE I. Physical and analytical data of compounds 1a d, 2a d and 3a d N/% Compd. R M.f. M.p./ C Yield/% Calcd. Found 1a Piperidine C 20 H 24 N 2 O b Morpholine C 19 H 22 N 2 O c Indole C 23 H 20 N 2 O d N-CH 3 piperazine C 20 H 25 N 3 O a Piperidine C 37 H 42 N 4 O b Morpholine C 35 H 38 N 4 O c Indole C 43 H 34 N 4 O d N-CH 3 piperazine C 37 H 44 N 6 O a Piperidine C 37 H 42 N 4 O 2 S b Morpholine C 35 H 38 N 4 O 4 S c Indole C 43 H 34 N 4 O 2 S d N-CH 3 piperazine C 37 H 44 N 6 O 2 S Preparation of 1,3-bis-(3-phenoxy- -piperidin-1-ylbenzyl urea (2a) To an aqueous solution of urea (0.1 mol, 6.0 g in 20 ml of water), ice-cooled piperidine (0.05 mol, 4.25 g) was added and stirred for 30 min. 3-Phenoxybenzaldehyde (0.05 mol, 9.9 g) was then added and the mixture was stirred for 2 h, at 5 ºC in an ice-bath and left for one day at room temperature. The resulting solid was isolated and crystallized from methanol. Compound 2a: yield 72 %, m.p. 172 ºC, Anal. Calcd. for C 37 H 42 N 4 O 4 : C, 75.25; H, 7.11; N, 9.49 %; Found: C, 75.25; H, 7.10; N, 9.49 %. IR (KBr) max 1701 (C=O), 3423 ( NH) cm -1.NMR 5.00 (2H, s, Ar CH+CH),9.65 (2H, s, NH + NH), (10H, m, Ar H). The mass spectrum indicated the molecular ion peak at m/z 590. The reaction procedure leading to 2a was then extended to the syntheses of 2b, 2c and 2d.The physical data of the obtained compounds 2a d are listed in Table I. Preparation of 1,3-bis-(3-phenoxy- -piperidin-1-ylbenzyl)thiourea (3a) A mixture of thiourea (0.1 mol, 7.6 g), piperidine (0.05 mol, 4.25 g) and water (20 ml) was stirred to obtain a clear solution. To this ice-cold solution, 3-phenoxybenzaldehyde (0.05 mol, 9.9 g) was added. The reaction mixture was stirred for 2 h in an ice-bath and left overnight at room temperature. The thus obtained white solid was isolated and crystallized from methanol. Compound 3a: yield 73 %, m.p. 165 ºC, Anal. Calcd. for C 37 H 42 N 4 O 2 S: C, 73.26; H, 6.93; N, 9.24 %; Found: C, 73.24; H, 6.90; N, 9.21 %. IR (KBr) max 1174 (C=O), 3330 ( NH) cm -1.NMR 9.92 (1H, s, NH), (10H, m, Ar H). The mass spectrum indicated the molecular ion peak at m/z 606. The reaction procedure leading to 3a was then extended to the syntheses of 3b, 3c and 3d.The physical data of the obtained compounds 3a d are listed in Table I.

4 1166 VASOYA et al. RESULTS AND DISCUSSION Antitubercular activity. All the compounds were screened against Mycobacterium tuberculosis strain H 37 Rv at a concentration 6.25 g/ml in BACTEC 12B medium using BACTEC 460-radiometric system. The standard drug used was rifampin. It could be observed that compounds 1a, 1b, 2c, 3c and 3d had higher activity than the standard. The screening results are given in Table II. TABLE II. Antitubercular and antimicrobial screening results of compounds 1a d, 2a d and 3a d Antitubercular Antimicrobial activity, zones of inhibition in mm Compd. activity, % of inhibition E. coli P. vulgaris B. megaterium S. aureus A. niger 1a b c d a b c d a b c d Amoxycillin Benzyl penicillin Ciprofloxacin Erythromycin Griseofulvin Antimicrobial activity. The antimicrobial activity was assayed using the cup-plate agar diffusion method 11 by measuring the zone of inhibition in mm. All the compounds were screened in vitro for their antimicrobial activity against a variety of bacterial strains, i.e., Bacillus megaterium, Escherichia coli, Proteus vulgaris, Staphylococcus aureus, and the fungi Aspergillus niger at a concentration of 40 g/ml. Standard drugs, i.e., amoxycillin, benzyl penicillin, ciprofloxacin, erythromycin and griseofulvin, were used for comparison purposes (Table II). It can be observed that compounds 1c, 1d and 3d were active against E. coli; compounds 1c, 2a and 3c were active against P. vulgaris; compounds 1b, 2c and 2a were active against B. megaterium; compounds 1a, 1b, 2b, 2c, 3a and 3b were active against S. aureus and compounds 1a, 1c, 1d, 2b, 3a and 3c displayed maximum activity against A. niger.

5 SYNTHESIS OF BIOACTIVE MANNICH BASES 1167 Acknowledgement: The authors wish to thank Professor and Head of the Deparment of Chemistry, Saurashtra University, Rajkot for providing the facilities. The authors are thankful to R.S.I.C. Chandigarh and C. D. R. I. for the spectral and analytical data. We are also thankful to the Tuberculosis Antimicrobial Acquisition Coordinating Facility (TAACF) for providing the antitubercular screening data. IZVOD SINTEZA AMINOBENZILOVANIH MANIHOVIH BAZA IZ JEDIWEWA S AKTIVNIM VODONIKOM U CIQU DOBIJAWA POTENCIJALNIH BIOAKTIVNIH AGENASA KAO PRIMER ZELENE HEMIJE S.L.VASOYA,P.T.CHOVATIA,D.H.PUROHITi H. S. JOSHI Department of Chemistry, Saurashtra University, Rajkot , Gujarat, India Opisana je efikasna metoda sinteze aminobenzilovanih Manihovih baza sa visokim prinosima. Sinteze se odigravaju u vodenoj sredini na 0 ºC. Jediwewa pokazuju umerenu antituberkuloznu i antimikrobnu aktivnost. (Primqeno 22. jula, revidirano 13. decembra 2004) REFERENCES 1. R. Carniar, G. Kirsh, M. Wierzbicki, K. Lepae, Eur. J. Med. Chem. 15 (1980) J. R. Dimmocic, S. K. Raghavan, B. M. Logan, G. E. Bigam, J. Med. Chem. 18 (1983) H. Henry, S. C. Etery, G. Papageovgiu, K. F. Wilkins, Tetrahedron Lett. 29 (1998) J. S. Flower, J. Org. Chem. 42 (1977) K. Nimavat, K. Popat, S. Vasoya, H. S. Joshi, J. Indian. Chem. Soc. 80 (2003) A. N. Mohamed Kasim, G. Venkatesa Prabhu, Asian J. Chem. 12 (2000) T. Kuwabe, S. Okuyama, S. Hashimoto, Jpn. Kokai Tokkyo Koho JP, 10 (1998), 114, 755. Appl. 1996, 96/266, D. R. Rae, S. G. Gibson, PCT. Int. Appl. WO 98, 21, 206, EP. Appl. 1996, 96/203, 175 C. A. 129 (1998) 27899A 9. R. Valarmathi, S. Karpagam, B. Jayaker, Indian J. Heterocyclic Chem. 10 (2000) G. Gautam Shenoy, Mohan Kotian, A. R. Bhatt, Indian J. Heterocyclic Chem. 9 (2000) A. L. Barry, The Antimicrobial Susceptibility Test: Principle and Practices, Lea and Febiger Philadelhia, Pa. USA, 1976, p. 180 [Biol Abstr. 64, (1977), 25183].