Int J Pharm Pharm Sci, Vol 6, Issue 9, 418-421Original Article
SYNTHESIS, CHARACTERIZATION AND IN VITRO ANTIMICROBIAL EVALUATION OF SOME NEW AMIDES OF THIOMORPHOLINE CARBOXYLATE
KUMARASWAMY B, RANJITH KUMAR T, NARSIMHA S, VASUDEVA REDDY N*
Department of Chemistry, Kakatiya University, Warangal 506009 India.
Email: vasujac3@gmail.com
Received: 05 Aug 2014 Revised and Accepted: 07 Sep 2014
ABSTRACT
Objective: Synthesis and antimicrobial evaluation of some new amides of Thiomorpholine caboxylate.
Methods: A series of new amides of Thiomorpholine caboxylate were synthesized by reacting 4-tert-butyl 2-methyl thiomorpholine-2,4-dicarboxylate 1,1-dioxide with primary amines in presence of Trimethyl aluminum in toluene at ambient temperature in good yields. 4-tert-butyl 2-methyl thiomorpholine-2,4-dicarboxylate 1,1-dioxide was synthesized by reacting tert-butyl thiomorpholine-4-carboxylate 1,1-dioxide with methyl chloroformate in presence of LiHMDS (1M in THF) at -78oC for the first time. The newly synthesized compounds were characterized by IR, 1HNMR, 13C NMR, Mass spectral studies and elemental analysis.
Results: A series of new amides of Thiomorpholine carboxylate were synthesized in good yields and all the compounds were screened for their In-vitro antimicrobial activities.
Conclusion: Preliminary results revealed that the synthesized compounds were showed moderate to good antibacterial and antifungal activity.
Keywords: Antimicrobial activity, Thiomorpholine, Trimethylaluminum, LiHMDS.
INTRODUCTION
Thiomorpholine units and amides of various heterocyclic compounds have attracted much attention for their remarkable pharmacological activities and have been explored as one of the best pharmacophores. Thiomorpholine derivaties have diverse biological activities that include DPP-IV inhibitors [1], anti-inflammatory [2], antioxidant [3-4], anti-microbial[5], hypertensive [6], anaesthatic [7], antiplatelet[8], antibacterial & Cytotaxin [9], anti-cancer [10], analgesic & hypothertic [11], antimycobacterial [12] and hypnotonic [13]. Considering the above facts and our search on Thiomorpholine linked biologically potent molecules, we herein report the synthesis of some new amides of Thiomorpholine Carboxylate and their microbial activity.
MATERIALS AND METHODS
All reagents and solvents were purchased from commercial suppliers and were purified and dried when necessary by standard techniques. The structures of newly synthesized compounds were established on the basis of, 1H NMR, FTIR, 13C NMR, mass spectral data and elemental analysis. The 1HNMR spectra were recorded on Brucker 300 and 400MHz spectrometer using TMS as internal standard. The Chemical shifts values are given in δ ppm. The FTIR spectra were recorded by using Perkin Elmer FTIR spectrometer using a thin film on KBr pellets and frequencies were expressed in cm-1. The Mass spectra were recorded by the EI process. The elemental analyses were performed on Perkin Elmer CHNS/O analyzer 2400. Melting points were determined on open capillaries using a cintex melting point apparatus and are uncorrected. Follow up of the reactions and checking the purity of the compounds was made by thin layer chromatography (TLC) on silica gel precoated aluminum sheets (Type 60 GF254; Merck; Germany) and the spots were detected by exposure to UV lamp at λ 254 nm for few seconds.
The synthesis of thiomorpholine moiety was reported by several groups and N-substituted thiomorpholines were reported [14]. The reactions on C’s of thiomorpholines are very few. In this work, we are reporting the synthesis of thiomorpholine carboxylate amides for the first time. The synthetic route for thiomorpholine carboxylate and amides is represented in scheme 1. The reaction of Compound-2 with methylchloroformate in presence of LiHMDS (1M in THF) resulted thiomorpholine carboxylate in excellent yield (98%). Compound-3 was treated with different amines in presence of Trimethyl aluminum (2M in Toluene) to afford new amide derivatives of thiomorpholine carboxylate (4a-j) in good yields.
Scheme 1: Synthetic route for new amides of Thiomorpholine carboxylate
Experimental
Synthesis of N-tert-butyloxycarbonyl thiomorpholine, 1
A solution of BOC2O (21.16g, 97 mmol) in dichloromethane (100 mL) was added to a solution thiomorpholine (10 g, 97 mmol) and triethylamine (16.23 mL, 116 mmol) in dichloromethane (500 mL). The mixture was stirred for 1 hour at room temperature and monitored by TLC. Ethyl acetate (400 mL) was added and the organic solution was washed with citric acid (3X250 mL, 1M), water (3X250 ml), brine (250 ml), dried over anhydrous sodium sulphate and evaporated in vacuo to afford N-tert-butyloxycarbonyl thiomorpholine, 1 as a colourless solid (19.5g, 99%).
Synthesis of tert-butyl thiomorpholine-4-carboxylate 1,1-dioxide, 2
N-tert-butyloxycarbonyl thiomorpholine (15 g, 73.89 mmol) was dissolved in dichloromethane (500 ml), m-chloroperbenzoic acid (25.49 g, 147.78 mmol) was gradually added while cooled with ice bath. The reaction mixture was stirred at room temperature for 12h. After completion of reaction, was added a saturated aqueous solution of sodium thiosulfate, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude. The crude was purified by column chromatography using 30-35% ethyl acetate in hexane as eluent to afford tert-butyl thiomorpholine-4-carboxylate 1,1-dioxide, 2 as off white solid.
Synthesis of 4-tert-butyl 2-methyl thiomorpholine-2,4-dicarboxylate 1,1-dioxide, 3
To a stirred solution of tert-butyl thiomorpholine-4-carboxylate 1,1-dioxide (42.55 mmol) in THF (300 mL) was added dropwise 1M solution of LiHMDS (42.55 mmol) at -78oC and the resulting reaction mixture was stirred under the nitrogen atmosphere for 1h. Methylchloroformate (42.55 mmol) was added drop wise to the above reaction mixture and stirred for 2h at -780C. The reaction mixture was added to NH4Cl solution (200 mL) and the product was extracted with EtOAc (3 x 150 mL) to obtain crude compound. The crude was recrystalized from diethylether, filtered and dried under vacuum to afford 4-tert-butyl 2-methyl thiomorpholine-2,4-dicarboxylate 1,1-dioxide, 3 as off white solid.
General Method for synthesis of 4a-j [15]
To a stirred solution of alkylamine (0.34 mmol) in Toluene was added Trimethylaluminum (2M in Toluene, 1.02 mmol) at 00C and allowed to stir for 15 min. A solution of 4-tert-butyl 2-methyl thiomorpholine-2,4-dicarboxylate 1,1-dioxide (0.34 mmol) in toluene was added drop wise to the reaction mixture under N2 and stirred for overnight at room temperature. The reaction mixture was poured into crushed ice, added 2N HCl, basified to pH 9- 10 with NH4OH and organic phase was separated.
The aqueous phase was washed with more CH2Cl2 the combined organic phases were washed with brine, dried over Na2SO4 and concentrated. The crude was chromatographed on silica gel (100-200 mesh), eluting with a gradient mixture of (30-35%) ethylacetate in hexane as eluent, giving (4a-f) as pure compounds (Table 1).
Table 1: It represents molecular formulas and yields of final compounds (4a-j)
| S. No. | Compound | R | Molecular Formula (4a-j) | Molecular Weight | Yield (%) |
| 1 | 4a | C18H26N2O5S | 382.474 | 85 | |
| 2 | 4b | C17H22N4O6S | 410.445 | 82 | |
| 3 | 4c | C17H24N2O5S. | 368.448 | 90 | |
| 4 | 4d | C17H24N2O6S | 384.44 | 84 | |
| 5 | 4e | C18H26N2O5S | 382.474 | 88 | |
| 6 | 4f | C22H26N2O5S | 430.517 | 89 | |
| 7 | 4g | NH2-NH2. H2O | C10H19N3O5S | 293.340 | 86 |
| 8 | 4h | C18H26N2O5S | 382.474 | 88 | |
| 9 | 4i | C18H26N2O5S | 382.474 | 84 | |
| 10 | 4j | C16H22N2O6S | 370.421 | 92 |
Spectral data
N-tert-butyloxycarbonyl thiomorpholine, 1: Yield (99%); Offwhite solid: 1HNMR (CDCl3, 300 MHz): 3.71-3.64 (m, 4H), 2.60-2.52 (m, 4H), 1.45 (s, 9H); ESI-MS 148 (M+- t-Butyl)
tert-butyl thiomorpholine-4-carboxylate 1,1-dioxide, 2:Yield (89%); Off white solid; M. P: 157 - 159 oC: 1H NMR (CDCl3, 300Mz): δ 4.0 - 3.9 (m, 4H), 3.10 - 2.90 (m, 4H), 1.44 (s, 9H): ESI-MS: 180 (M+- t-Butyl)
4-tert-butyl 2-methyl thiomorpholine-2,4-dicarboxylate 1,1-dioxide,3:Yield (98%); Off white Solid; M. P: 110-113oC; 1H NMR (DMSO-d6, 400MHz): δ 4.37 (br, 1H), 4.11-3.86 (m, 3H), 3.72-3.47 (br, 4H), 3.41- 3.36 (br, 1H), 3.26-3.25(m, 1H), δ 1.41 (s, 9H); ESI-MS: 180 (M+- t-Butyl)
tert-butyl 2-(phenethylcarbamoyl) thiomorpholine-4-carboxylate 1,1-dioxide, 4a: Offwhite solid; M. P: 95-98oC; FTIR (KBr, cm-1);3385, 3072, 1685, 1585, 1273, 1106, 757; 1H NMR (DMSO-d6, 400MHz): δ 8.40-8.20 (br, 1H), 7.40- 7.10 (m, 5H), 4.18 - 3.90 (m, 2H), 3.80 - 3.50 (m, 5H), 3.20 - 3.10 (m, 2H), 2.80 - 2.60 (m, 2H), 1.41 (s, 9H). 13C–NMR (DMSO, 125Mz):δ 163.42 (CONH), 153.18 (COBoc), 139.02 (Ar-CH),128.63(2,Ar-CH),128.36(2,Ar-CH), 126.18 (CH), 80.00 (-(CH3)3CO-), 63.01(CH), 50.81(CH2), 49.25(CH2), 45.66 (CH2), 40.58 (NHCH2), 34.85 (Ar-CH2), 27.79 (CH3):EI-MS (m/z): 327(M+- t-Butyl); Anal. Cald. for C18H26N2O5S; C, 56.52; H, 6.85; N, 7.32; O, 20.92; S, 8.38; Found: C, 56.48; H, 6.81; N, 7.36; O, 20.88; S, 8.34
tert-butyl 2-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl) carbamoyl) thiomorpholine -4-carboxylate 1,1-dioxide, 4b; Offwhite solid. M. P: 258- 260oC; FTIR (KBr, cm-1): 3388, 2978, 1693,1566, 1295, 868, 710; 1H NMR (DMSO-D6, 400MHz): δ 10.62 (s, 1H), 10.55 (s, 1H), 10.22-10.18(br, 1H), 7.46 (s, 1H), 7.02-6.85 (br, 1H), 6.87-6.85 (d, j= 8.0Hz, 1H), 4.40-4.20 (br, 2H), 4.02 -3.90(m, 1H), 3.80-3.70 (m, 1H), 3.70-3.55 (m, 1H), 3.42.-3.30 (m, 1H), 3.22-3.16 (m, 1H), 1.41 (s, 9H). EI-MS (m/z): 355(M+- t-Butyl); Anal. Cald. for C17H22N4O6S: C, 49.75; H, 5.40; N, 13.65; O, 23.39; S, 7.81;Found; C, 49.68; H, 5.46; N, 13.60; O, 23.32; S, 7.78
tert-butyl 2-(benzylcarbamoyl)thiomorpholine-4-carboxylate 1,1-dioxide, 4c: Offwhite solid; M. P: 85-90oC; FTIR (KBr, cm-1): 3345, 3088, 1687,1609,1267,1100, 833, 751: 1H NMR (DMSO-D6, 400MHz): δ 8.80-8.65 (br, 1H), 7.4-7.2(m, 5H), 4.5-4.1 (br, 4H), 3.95-3.85 (m, 1H), 3.80-3.50 (m, 3H), 3.20-3.10 (m, 1H), 1.35(s, 9H). EI-MS (m/z): 313 (M+- t-Butyl); Anal. Cald. for C17H24N2O5S; C, 55.42; H, 6.57; N, 7.60; O, 21.71; S, 8.70; Found; C, 55.39; H, 6.50; N, 7.58; O, 21.61; S, 8.65.
tert-butyl 2-[(2-hydroxy-6-methylphenyl) carbamoyl] thio morpholine-4-carboxylate 1,1-dioxide, 4d; Light yellow solid; M. P; 90- 92; FTIR (KBr, cm-1): 3601, 3341,3064, 1693,1601,1521,1203, 850, 711 1H NMR (DMSO-d6, 400MHz): δ 9.44(s, 1H), 9.35-9.18(b, 1H), 6.98 (t, j= 7.6Hz, j= 8Hz,1H), 6.71-6.64 (dd, j= 7.6Hz, j= 8.0Hz, 2H), 4.40-4.30(m, 1H), 4.25-4.15 (m, 2H), 4.00-3.70 (m, 2H), 3.55-3.40 (m, 2H), 3.20-3.10 (m, 1H) 2.08 (s, 3H),1.5-1.25 (br, 9H); EI-MS (m/z):329(M+- t-Butyl); Anal. Cald. for C17H24N2O6S; C, 53.11; H, 6.29; N, 7.29; O, 24.97; S, 8.34;Found; C, 53.08; H, 6.26; N, 7.27; O, 24.94; S, 8.30
tert-butyl 2-(m-tolylcarbamoyl)thiomorpholine-4-carboxylate 1,1-dioxide, 4e: Brownsolid: M. P; 82- 84oC; FTIR (KBr, cm-1): 3376, 3068, 1696,1606,1270,1099, 847, 751: 1H NMR (DMSO-d6, 400 MHz): δ 8.80-8.60 (br, 1H), 7.25 (s, 1H), 7.20-7.00 (m, 3H), 4.50-4.11 (m, 3H), 4.10-3.80 (m, 2H), 3.80-3.50 (m, 1H), 3.20-3.10 (m, 2H), 2.25 (s, 3H), 1.40 (s, 9H); EI-MS (m/z):327(M+- t-Butyl); Anal. Cald. for C18H26N2O5S; C, 56.52; H, 6.85; N, 7.32; O, 20.92; S, 8.38; Found: C, 56.48; H, 6.80; N, 7.28; O, 20.94; S, 8.34.
tert-butyl 2-([1,1'-biphenyl]-2-ylcarbamoyl)thiomorpholine-4-carboxylate 1,1-dioxide, 4f: Offwhite solid; M. P: 148-150; FTIR (KBr, cm-1): 3359, 3072, 1695,1588,1269,1098,1008, 759: 1H NMR (DMSO-d6, 300MHz): δ 9.65-9.58 (br, 1H), 7.7-7.50(br, 1H), 7.50-7.30 (m, 8H), 4.4-4.0 (br, 3H), 3.80-3.40 (br, 3H), 3.29-3.10 (m, 1H), 1.4 (s, 9H); EI-MS (m/z):375 (M+- t-Butyl); Anal. Cald. for C22H26N2O5S; C, 61.38; H, 6.09; N, 6.51; O, 18.58; S, 7.45; Found; C, 61.30; H, 6.15; N, 6.50; O, 18.52: S, 7.42.
tert-butyl 2-(hydrazinecarbonyl)thiomorpholine-4-carboxylate 1,1-dioxide, 4g: Offwhite solid; M. P; 120- 125; FTIR (KBr, cm-1): 3348, 2933, 1689, 1590, 1426, 1298, 875, 611: 1H NMR (DMSO-d6, 400MHz): δ 9.50- 9.30 (b, 1H), 4.50-4.30 (m, 2H), 4.20-4.00 (b, 1H), 4.00-3.90 (b, 1H), 3.80-3.60 (m, 2H), 3.60-3.40 (m, 2H), 3.15-3.10 (m, 1H), 1.40 (s, 9H), EI-MS (m/z): 238 (M+- t-Butyl); Anal. Cald. for C17H24N2O6S; C, 53.11; H, 6.29; N, 7.29; O, 24.97; S, 8.34;Found; C, 53.08; H, 6.26; N, 7.27; O, 24.94; S, 8.30
tert-butyl 2-((4-methylbenzyl)carbamoyl)thiomorpholine-4-carboxylate 1,1-dioxide, 4h: Offwhite solid; M. P; 98- 100; FTIR (KBr, cm-1): 3333, 3068, 1696,1511, 1456, 1256, 847, 769: 1H NMR (DMSO-d6, 400MHz): δ 8.60-8.80 (b, 1H), 7.35 (d, J=8.2 Hz, 2H), 7.05 (d, J=8.2 Hz, 2H), 4.40-4.11 (m, 3H), 4.10-3.80 (m, 2H), 3.80-3.50 (m, 2H), 3.20-3.10 (m, 2H), 2.25 (s, 3H), 1.40 (s, 9H): EI-MS (m/z): 327(M+- t-Butyl); Anal. Cald. for C17H24N2O6S; C, 53.11; H, 6.29; N, 7.29; O, 24.97; S, 8.34;Found; C, 53.08; H, 6.26; N, 7.27; O, 24.94; S, 8.30
tert-butyl 2-((3,5-dimethylphenyl)carbamoyl)thiomorpholine-4-carboxylate 1,1-dioxide, 4i: Offwhite solid; M. P; 105-108; FTIR (KBr, cm-1):3364, 3092, 1696,1608,1455,1211, 867, 697: 1H NMR (DMSO-d6, 400MHz): δ 9.00 (s, 1H), 7.30 (s, 2H), 6.70(s, 1H), 4.40-4.30(m, 1H), 4.25-4.15 (m, 2H), 4.00-3.70 (m, 2H), 3.55-3.40 (m, 1H), 3.20-3.10 (m, 1H) 2.25 (s, 6H),1.41 (s, 9H); EI-MS (m/z): 327(M+- t-Butyl); Anal. Cald. for C17H24N2O6S; C, 53.11; H, 6.29; N, 7.29; O, 24.97; S, 8.34;Found; C, 53.08; H, 6.26; N, 7.27; O, 24.94; S, 8.30
tert-butyl 2-((4-hydroxyphenyl)carbamoyl)thiomorpholine-4-carboxylate 1,1-dioxide, 4j: Offwhite solid; M. P; 95-98; FTIR (KBr, cm-1): 3625, 3385, 3084,1674,1482, 1451, 981, 741: 1H NMR (DMSO-d6, 400MHz): δ 9.50(s, 1H), 9.40-9.20(b, 1H), 7.33 (d, J=6.8 Hz, 2H), 6.67 (d, J=6.9 Hz, 2H), 4.40-4.00 (m, 3H), 4.00-3.60 (m, 2H), 3.55-3.40 (m, 1H), 3.20-3.10 (m, 1H), 1.42(s, 9H); EI-MS (m/z): 315(M+- t-Butyl); Anal. Cald. for C17H24N2O6S; C, 53.11; H, 6.29; N, 7.29; O, 24.97; S, 8.34;Found; C, 53.08; H, 6.26; N, 7.27; O, 24.94; S, 8.30.
Table 2: Zone of inhibition (mm) data of synthesized compounds (4a-j)
| S. No. | Compound | B. subtilis | S. aureus | E. coli | S. typhi | A. niger | C. albicans |
| 1 | 4a | 8 | 7 | 7 | 6 | 10 | 8 |
| 2 | 4b | 11 | 10 | 12 | 11 | 13 | 11 |
| 3 | 4c | 9 | 6 | 8 | 4 | 9 | 6 |
| 4 | 4d | 7 | 5 | 9 | 6 | 11 | 9 |
| 5 | 4e | 9 | 4 | 8 | 6 | 10 | 8 |
| 6 | 4f | 7 | 5 | 6 | 4 | 12 | 8 |
| 7 | 4g | 9 | 7 | 10 | 7 | 8 | 6 |
| 8 | 4h | 7 | 6 | 9 | 8 | 10 | 8 |
| 9 | 4i | 8 | 7 | 9 | 6 | 11 | 8 |
| 10 | 4j | 8 | 6 | 8 | 4 | 12 | 7 |
| 11 | Control | - | - | - | - | - | - |
| 12 | A | 16 | 15 | 19 | 16 | - | - |
| 13 | B | - | - | - | - | 19 | 17 |
Control=DMSO, A=Ciprofloxacin and B=Ketoconazole
RESULTS AND DISCUSSION
Antibacterial activity
The antibacterial activity of all the synthesized compounds (4a-j) was examined against different Gram‐positive (Bacillus subtilise and Staphylococcus aureus) and Gram‐negative (Escherichia coli and Salmonella typhii) organisms by measuring zone of inhibition. The antibacterial activity was performed by Agar diffusion method at the concentration level of 250μg/ml. Ciprofloxacin was used as the standard drug at a concentration of 250μg/ml. Nutrient agar was used as culture media and DMSO was used as the solvent control. The results of the antibacterial activity are shown in Table 2.
Antifungal activity
The antifungal activity of all the synthesized compounds (4a‐j) was examined against Aspergillus niger and Candida albicans by measuring zone of inhibition. The antifungal activity was performed by Agar diffusion method at the concentration level of 250μg/ml. Ketoconazole was used as a standard drug at a concentration of 250μg/ml. Sabouraud dextrose agar was used as culture media and DMSO was used as solvent control. The results of the antifungal activity are shown in Table 2.
CONCLUSION
In accordance with the data obtained from antimicrobial activity, 4b showed good antimicrobial activity against the tested microbes among all the synthesized amides and rest of the compounds showed moderate antimicrobial activity against tested microbes.
ACKNOWLEDGEMENT
The authors are thankful to Head of the Department, Kakatiya University, Warangal for providing necessary research facilities and also to the Director, IICT, for providing spectral data.
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