Synthesis, Characterization and Antimicrobial Screening of NewCyclic Imides
Kulveer Singh1, Suman Kumari1, Y.K. Gupta2*
1Research Scholar, School of Applied Sciences Singhania University Pacheri Bari, Jhunjhunu (Raj.), India
2Head Department of Chemistry, B K Birla Institute of Engineering and Technology, Pilani, Rajasthan, India
*Corresponding Author E-mail: ykgbkbiet@rediffmail.com,ykgbkbiet@yahoo.com,ykgbkbiet123@gmail.com
ABSTRACT:
The Cyclic imides and their Derivatives have been attracted significantly more attention of organic and medicinal chemists due to their antimicrobial activities. The derivatives of six member cyclic imides were synthesized by the action of glutaric anhydride with different substituted aromatic amines to obtained 4-(N-phenylcarbamoyl) butanoic acid. These intermediates undergo ring closer with acetyl chloride furnished six member cyclic imides derivatives. All these derivatives were screened for their antimicrobial activities.
KEYWORDS:Six member cyclic
imides, glutarimide, 4-(N-phenylcarbamoyl) butanoic acid,N- Phenyl.
1. INTRODUCTION:
Cyclic imides have been attracted much more attention of organic and medicinal chemists due to their biological activities, most of them are extensively used as analgesic1, anti-nociceptive agents2 or as reactants for polymer synthesis3. An imide nucleus can be also found in a structure of anxiolytic, antimicrobial, anticancer and anti-inflammatory substances4-6. The cyclic imides like succinimides, male imides, phthalimides, glutarimides embracing the foremost part in the organic synthesis. The different substituted six membered glutarimide derivatives are hydrophobic nature which reflects antibacterial and antifungal potencies. Some of the glutarimide drugs affected the thymine nucleosides, uracil transport in the biological membranes7. The influence of poly glutarimides PMMA thermal stability noticeably improves the imidization8by IRTF analysis9. Natural products like glutarimide alkaloids isolated from Crotonpullei species which gives preeminent antibacterial and antifungal activities10.
The optimistic effects of glutarimides actively found on spinal neurons11, brain metabolism12, mitochondrial respiration13. The different substituted heterocyclic imides including glutarimides were prepared from cyclic anhydrides14, by using PPA15, Baylis Hillman adducts16, tandem process17, succinic and glutaric acids 18. Thus the selective synthesis of glutarimide analogous has been highlighted in this research paper19-20.
2. EXPERIMENTAL:
2.1 Material Methods
Commercially available chemicals and solvents were used as received from BDH and Merck. The melting points of the new compounds were recorded in open glass capillaries and were uncorrected. IR spectra in KBr (pallets) were recorded on Shimadzu-8400S and ATR Brucker alpha FT-IR spectrophotometer. 1H NMR, 13C NMR spectra were recorded on 300 MHz, 500.13 MHz and 125.77 MHz by Brucker spectrophotometers. The reaction was monitored by thin layer chromatography which was performed by using pre-coated silica gel aluminum plates with mixture of diethyl ether and ethyl acetate 7:3 proportion. All the compounds 3a-j and 4a-j were synthesized in hours from the corresponding commercial available aromatic amines, glutaric anhydride, acetyl chloride and benzene
2.2 General procedure for Preparation of six membered cyclic imides
2.2.1 Preparation of 4-(N-phenylcarbamoyl) butanoic acid (3a-j):
To glutaric anhydride (10 m mole) benzene was added and heated under reflux with constant stirring for 15 to 20minutes till the solution becomes clear. Into this solution the primary aromatic amine (10 m mole) in 5 ml benzene was slowly poured with constant stirring for 15 to 20 minutes till the solution becomes homogenized. Upon evaporation of benzene the whitish amorphous powder of 4- (N- Phenyl carbamoyl) butanoic acid was obtained21. The experimental method diagrammatically shown in fig.1.
2.2.1.1 4-(phenyl carbamoyl) butanoic acid (3a):
Brownish powder, M.F. C11H13NO3, Mol. Wt. 207.23, M.P. 110 ºC
2.2.1.2 4-(4-bromophenylcarbamoyl) butanoic acid
(3b): Whitish brown powder, M. F. C11H12BrNO3, Mol. Wt. 286.12, M.P. 139 ºC
2.2.1.3 4-(4-chlorophenylcarbamoyl) butanoicacid (3c):
Brown powder, M.F.: C11H12ClNO3, Mol. Wt. 241.67, M.P. 109 °C
2.2.1.4 4-(p-tolylcarbamoyl) butanoic acid (3d):
Cream colour powder, M.F. C12H15NO3, Mol. Wt. 221.25, M.P. 148 ºC
2.2.1.5 4-(4-methoxyphenylcarbamoyl) butanoic acid (3e):
Brownish white powder, M.F. C12H15NO4, Mol. Wt. 237.25, M.P. 132 ºC
2.2.1.6 4-(4-fluorophenylcarbamoyl) butanoic acid (3f):
Brownish gray powder, M.F. C11H12FNO3, M.P. 112 ºC Mol. Wt. 225.22
2.2.1.7 4-(4-nitrophenylcarbamoyl) butanoic acid (3g):
Greenish gray powder, M.F. C11H12N2O5, Mol. Wt. 252.22, M.P. 122 ºC
2.2.1.8 4-(naphthalen-4-ylcarbamoyl) butanoic acid (3h)
Brown powder, M.F. C15H15NO3, Mol. Wt. 257.28, M.P. 143 ºC
2.2.1.9 4-(3-chloro-4-fluorophenylcarbamoyl) butanoic acid (3i):
Wheat colour powder, M.F. C11H11ClFNO3, Mol. Wt. 259.66, M.P. 111 ºC
2.2.1.10 4-(2,4,5-trichlorophenylcarbamoyl) butanoic acid (3j):
White powder, M.F. C11H10Cl3NO3, Mol. Wt. 310.56, 128 ºC
Refluxed at 90-110 ºC up to 15 - 20 minutes for both conditions
Figure1: Experimental display of the N-phenyl glutarimide Synthesis
Scheme - I: Preparation of N-phenyl Glutarimides
2.2.2 Preparation of N-Phenyl glutarimides:
The mixture of 4-(phenyl carbamoyl) butanoic acid and acetyl chloride (90 mmole) was reflux or 15 to 20 minute still the complete evolution of HCl gas. The reaction mixture was cooled at room temperature the solid product was obtained and purified by recrystallization from ethanol (scheme–I)
2.2.2.1 1-phenylpiperidine-2, 6-dione (4a):
Cream colour solid, yield (77.92%), m. p. 120-122 ºC, M.F. C11H11NO2, Mol. Wt. 189.21; IR (KBr): 1674, 1770, 971,1314, 1499, 1535, 1598 cm-1;
2.2.2.2 1-(4-bromophenyl) piperidine-2, 6-dione (4b):
Whitish brown solid, yield (82.94%), m. p. 144-146 ºC,M.F. C11H10BrNO2, Mol. Wt. 268.11; IR (KBr): 1695,1719, 2992, 1301, 1490, 1526, 1589, 1070 cm-1, 1H NMR(300 MHz, CDCl3, δ ppm): 7.40-7.55 (d, 4H, Ar-H), 1.87(m, 2H, -CH2-CH2-CH2-), 2.226 (t, 4H, imide)
2.2.2.3 1-(4-chlorophenyl) piperidine-2, 6-dione (4c):
Faded lavender solid, yield (86.70%), m. p. 123-125 ºC, M.F. C11H10ClNO2, Mol. Wt. 223.66; IR (KBr): 1726,1782, 2979, 1300, 1495, 1527, 1591, 1090 cm-1, 1H NMR (300 MHz, CDCl3, δ ppm): 7.25-7.58 (d, 4H, Ar-H), 1.98(m, 2H, -CH2-CH2-CH2-), 2.23 (t, 4H, imide)
2.2.2.4 1-p-tolylpiperidine-2, 6-dione (4d):
Marble colour solid, yield (77.07%), m. p. 179-181 ºC, M.F. C12H13NO2, Mol. Wt. 203.24; IR (KBr): 1698, 1746,2962, 1310, 1536, 1599, 1661 cm-1
2.2.2.5 1-(4-methoxyphenyl) piperidine-2, 6-dione (4e):
Brownish solid, yield (76.66%), m. p. 138-140 ºC, M.F. C12H13NO3, Mol. Wt. 219.24; IR (KBr): 1697, 1718, 2954,1302, 1515, 1536, 1600, 1272 cm-1
2.2.2.6 1-(4-fluorophenyl) piperidine-2, 6-dione (4f):
Brownish solid, yield (76.35%), m. p. 119-121 ºC, M.F. C11H10FNO2, Mol. Wt. 207.2; IR (KBr): 1696, 1722, 2961,1305, 1519, 1613, 1658, 1186 cm-1; 1H NMR (300 MHz, CDCl3, δ ppm): 7.6-7.55 (d, 4H, Ar-H), 1.68 (m, 2H, -CH2- CH2-CH2-), 2.15 (t, 4H, imide)
2.2.2.7 1-(4-nitrophenyl) piperidine-2, 6-dione (4g):
Cream yellow solid, yield (84.01%), m. p.
168-170 ºC, M.F. C11H10N2O4, Mol.
Wt. 234.21; IR (ATR): 1710, 1750,2960, 1300, 1520, 1590, 1600, 1500 cm-1
2.2.2.8 1-(naphthalen-4-yl) piperidine-2, 6-dione (4h):
Dark lavender solid, yield (83.61%), m. p. 153-155 ºC, M.F. C15H13NO2, Mol. Wt. 239.27; IR (ATR): 1651, 1703,2958, 1316, 1405, 1443, 1500, 1529, 1596 cm-1; 1H NMR (300 MHz, CDCl3, δ ppm): 7.30-7.57 (m, 6H, Ar-H), 1.62(m, 2H, -CH2-CH2-CH2-), 2.22 (t, 4H, imide)
2.2.2.9 1-(3-chloro-4-fluorophenyl) piperidine-2, 6-dione (4i):
Whitish brown solid, yield (91.30%), m. p. 104-106 ºC, M.F. C11H9ClFNO2, Mol. Wt. 241.65; IR (ATR): 1638, 1700, 2951, 1312, 1497, 1546, 1600, 1191, 1055 cm-1; 1H NMR (500.13 MHz, DMSO-d6, δ ppm): 7.34-7.92 (m, 3H, Ar-H), 1.80 (m, 2H, -CH2-CH2-CH2-), 2.28 (t, 4H, imide); 13C NMR (125.77 MHz, DMSO-d6, δ ppm): 20.72, 33.35, 35.75, 39.95, 117.19, 119.70, 120.82, 136.93, 152.35, 154.29, 171.42, 174.56
2.2.2.10 1-(2,4,5-trichlorophenyl) piperidine-2,6-dione (4j):
Pure white solid, yield (85.73%), m. p. 138-140 ºC, M.F. C11H8Cl3NO2, Mol. Wt. 292.55; IR (ATR): 1665, 1697,2968, 1306, 1457, 1513, 1570, 1076 cm-1; 1H NMR (500.13 MHz, CDCl3, δ ppm): 7.28-7.49 (d, 2H, Ar-H), 2.10 (m,2H, -CH2-CH2-CH2-), 2.27 (t, 4H, imide)
3. RESULTS AND DISCUSSION:
3.1 Chemistry:
The intermediate 3a-j compounds were prepared by the reaction of glutaric anhydride using aromatic amines. Theseries of cyclic imides 4a-j were synthesized in reasonable yields by condensation of intermediate 3a-j with acetylchloride formation of six membered cyclic imides was confirmed by IR, 13C NMR and 1H NMR and elementanalysis.
3.2 Antibacterial activities:
All the synthesized compounds 4a-j were Screened for their antibacterial activity against gram positive bacteriaBacillus Subtilis(MCMB-310) and gram negative bacteria E. Coli(MCMB-301) using DMF solvent. The bacterialcultures were purchased from ARI, Pune. Some of the compound illustrated moderate to good activities againstBacillus subtilisand E. colias shown in the table –1.
Table 1: Antibacterial activities of N-Phenyl Glutarimides.
|
Compound Code |
Gram +ve bacteria |
Gram -ve bacteria |
||||
|
Bacillus subtilis |
E. coli |
|||||
|
100μg/ml |
200μg/ml |
300μg/ml |
100μg/ml |
200μg/ml |
100μg/ml |
|
|
4a |
-- |
8.33±0.33 |
11±0.57 |
7.33±0.33 |
10.33±0.33 |
12.33±0.33 |
|
4b |
-- |
8.66±0.33 |
11±0.57 |
-- |
11.33±0.33 |
12.33±0.33 |
|
4c |
6.66±0.33 |
9±0.57 |
12.33±0.33 |
8.33±0.33 |
12.33±0.33 |
14.66±0.33 |
|
4d |
-- |
6±0.00 |
11.33±0.33 |
7±0.57 |
9±0.57 |
12±0.00 |
|
4e |
-- |
6±0.00 |
11±0.57 |
|
11.33±0.33 |
13.33±0.33 |
|
4f |
-- |
7.33±0.33 |
11.33±0.33 |
8±0.57 |
12.66±0.33 |
15.66±0.33 |
|
4g |
-- |
-- |
-- |
7.33±0.33 |
10.66±0.33 |
13±0.57 |
|
4h |
-- |
6±0.00 |
6.66±0.33 |
7.33±0.33 |
11±0.00 |
12±0.00 |
|
4i |
6±0.00 |
7.33±0.33 |
9.33±0.33 |
-- |
9.66±0.33 |
12.66±0.33 |
|
4j |
-- |
7.33±0.33 |
11±0.57 |
-- |
9.33±0.33 |
13.66±0.33 |
|
Control |
0 |
0 |
0 |
0 |
0 |
0 |
|
Ampicillin |
18.66±0.33 |
22.33±0.33 |
24±0.57 |
18.66±0.33 |
21±0.57 |
24±0.57 |
4. CONCLUSION:
A method for synthesis of glutarimide(4a-j) has been developed in good yield. All these compounds werecharacterized by their spectral analysis. Most of the compound exhibited moderate to good activity againstBacillus subtilisand E. coli. The synthesized compounds may be used for preparation of various heterocyclic systems.
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Received on 04.12.2017 Modified on 21.12.2017
Accepted on 26.12.2017 ©A&V Publications All right reserved
Research J. Science and Tech. 2017; 9(4): 691-694.