Synthesis, Characterization and Antimicrobial Activity of Some Schiff Bases of 2-amino-4-(4-chlorophenyl)–n-(3-furan-2-ylmethyl carboxamido) thiophenes
Monica Arora*, J. Saravanan, S. Mohan, Shivaji Bhattacharjee
Department of Pharmaceutical Chemistry, PES College of Pharmacy, Bangalore-50, Karnataka, India.
*Corresponding Author E-mail: monicaarora15@gmail.com
ABSTRACT:
2-amino-4-(4-chlorophenyl)-N-(3-furan-2-ylmethyl carboxamido) thiophenes was synthesized using versatile Gewald reaction .First step is preparation of furfuryl cyanoacetamide which was carried out by condensation of furfuryl amine and ethyl cyano acetate which was then reacted with p-chloro acetophenone, sulphur, diethyl amine to give 2-amino-4-(4-chlorophenyl)-N-(3-furan-2-yl methyl carboxamido) thiophene (SM-4) later the compound was treated with twelve different substituted aryl aldehydes to yield twelve new Schiff bases(SM 4a-4l). The compounds were characterized IR, 1H NMR and mass spectral data and screened for antimicrobial activity.
KEYWORDS: Synthesis, Thiophenes, Schiff bases, Spectral analysis, Antimicrobial activity.
A large number of medicinal compounds which have been discovered belong to heterocycles containing Nitrogen and Sulphur. Various pharmacological activity of these heterocycles has helped the implementation of new approaches towards the discovery of novel drugs. Thiophenes and its derivatives are an important class of heterocyclic compounds specifically, the benzo[b] thiophenes reported to possess wide spectrum of biological properties such as antimicrobial1, anti- inflammatory2, CNS depressant activity3, antifungal activity4, analgesic5, anti-tumor6, alkaline phosphatase inhibitor7.
Similarly Schiff Bases derivatives also have been reported to possess an array of biological activities therefore attracts interest both for synthetic and biological point of view. Schiff base exhibits antimicrobial8, ulcerogenic9, anticonvulsant10, CNS depressant activities11. Generally, In Pharmaceutical field new drugs are discovered by molecular modification of the lead compound of established activity. So far, a range of new thiophenes have been synthesized and screened for their biological activity.
The encouraging results prompted us design and prepare new 2-amino benzo[b] thiophenes by adaptation of well known and versatile Gewald reaction13 and their Schiff bases where in two moieties incorporating heterocycles are linked together through azomethine (-CH=N-) grouping and to study their anti microbial activity.
MATERIAL AND METHODS:
Chemicals:
Furfuryl amine, ethyl cyanoacetate, , p-chloro acetophenone, acetic anhydride, sulphur, diethyl amine, 4’-dimethyl amino benzaldehyde, 3’,4’5’-trimethoxy benzaldehyde, 3’,4’-dimethoxy benzaldehyde, 2’-nitro benzaldehyde,3’-nitro benzaldehyde, 2’-chloro benzaldehyde, 4’–chloro benzaldehyde, 4’-hydroxy benzaldehyde, 4’-hydroxy 3’-methoxy benzaldehyde, 2’-hydroxy benzaldehyde, 4’-methoxy benzaldehyde, 4’-dimethyl amino bezaldehyde, 4’methyl benzaldehyde were obtained from local dealer. All other chemical used were of laboratory grade.
EXPERIMENTAL:
Melting points were taken in open capillary tubes and are uncorrected. The purity of compounds was confirmed by thin layer chromatography using Merck silica gel 60 F254 coated aluminium plates. IR spectra were recorded on Shimadzu-FTIR Infrared spectrometer in KBr (νmax in cm−1). 1H NMR spectra were recorded in CDCl3 and DMSO-d6 on a Varian (300 MHz) spectrometer using TMS as internal standard and 13C NMR spectra were recorded in CDCl3 and in DMSO-d6 on a Varian (75 MHz) spectrometer. FABMS spectra were recorded on a JEOL SX 102/DA-6000 Mass spectrometer using argon/xenon (6 kv,10 mA) as the FAB gas.
Preparation of 3-(4-chlorophenyl)-2-cyano-N-(furan-2-ylmethyl) but-2-enamide:
Furfuryl cyanoacetamide was prepared by condensation of furfuryl amine and ethyl cyano acetate (1:1) by heating for 2 hours at 160o C. Furfuryl cyanoacetamide is further reacted with p-chloro acetophenone in presence of ammonium acetate (1gm) and glacial acetic acid (2ml) in benzene (100 ml) for 12 hours in dean stark apparatus with continuous separation of water. After 12 hours the reaction mixture was cooled, diluted with 10 ml of benzene and washed with sodium carbonate solution (10%w/v in water) and water successively and dried over anhydrous sodium sulphate. The solvent was removed under vacuum and the intermediate crude product obtained was immediately processed for the next step.
Preparation of 2-amino-4-(4-chlorophenyl)-N-(3-furan-2-ylmethyl carboxamido) thiophenes (SM-4):
To a mixture of 3-(4-chlorophenyl)-2-cyano-N-(furan-2-ylmethyl) but-2-enamide in alcohol (40ml) and sulfur (1.28gm) at 50oC, diethyl amine (7ml) was added dropwise with stirring. The reaction mixture was stirred for further 3 hours at same temperature. The reaction mixture was directly used for further derivatization.
Preparation of 2-[(substituted benzylidene) amino] 4-(4-chlorophenyl)-N-(3-furan-2-ylmethyl carboxamido) thiophenes. (SM-4a-4l):
A mixture of equimolar amount (0.01) of 2-amino thiophenes, benzaldehyde derivatives (a-l) in ethanol (40ml) along with catalytic amount of glacial acetic acid was refluxed for 4 hours. The reaction mixture was concentrated cooled, the solid obtained was filtered and recrystallized from ethanol to give Schiff base (SM-4a-4l). It was obtained 55-60% yield.
Scheme
Table -1 Physical data of 2-amino-4-(4-chlorophenyl)-N-(3-furan-2-ylmethyl carboxamido) thiophene. (SM-4)
|
Comp Code |
Molecular Formula |
M.W(g) |
Recrystalization Solvent |
M.P(OC) |
%Yield |
TLC Solvent |
Rf Value |
|
SM-4 |
C16H13ClN2O2S |
332 |
2-propanol |
181 |
45 |
Methanol: Chloroform(9:1) |
0.64 |
Table-2 Physical data of 2-[(substituted benzylidene) amino] 4-(4-chlorophenyl)-N-(3-furan-2-ylmethyl carboxamido) thiophenes.(SM-4a-4l)
|
Comp Code |
X |
Molecular Formula |
M.W (g) |
M.P (oC) |
% Yield |
T.L.C Solvent |
Rf Value |
|
SM-4a |
3’4’5’–trimethoxy benzaldehyde |
C26H23ClN2O5S |
510 |
206 |
69 |
Methanol: Chloroform (9:1) |
0.51 |
|
SM-4b |
3’4’–dimethoxy benzaldehyde |
C25H21ClN2O4S |
480.3 |
197 |
63 |
Methanol: Chloroform (9:1) |
0.71 |
|
SM-4c |
2’–nitro benzaldehyde |
C23H16ClN3O4S |
465.6 |
184 |
58 |
Methanol: Chloroform (9:1) |
0.63 |
|
SM-4d |
3’-nitro benzaldehyde |
C23H16ClN3O4S |
465.6 |
192 |
52 |
Methanol: Chloroform (9:1) |
0.58 |
|
SM-4e |
2’-chloro benzaldehyde |
C23H16Cl2N2O2S |
455.3 |
185 |
55 |
Methanol: Chloroform (9:1) |
0.70 |
|
SM-4f |
4’-chloro benzaldehyde |
C23H16Cl2N2O2S |
455.3 |
223 |
57 |
Methanol: Chloroform (9:1) |
0.49 |
|
SM-4g |
4’-hydroxy benzaldehyde |
C23H17ClN2O3S |
436.9 |
208 |
50 |
Methanol: Chloroform (9:1) |
0.50 |
|
SM-4h |
4’hydroxy 3’methoxy benzaldehyde |
C24H19ClN2O4S |
467.4 |
212 |
59 |
Methanol: Chloroform (9:1) |
0.41 |
|
SM-4i |
2’hydroxy benzaldehyde |
C23H17ClN2O3S |
436.9 |
214 |
47 |
Methanol: Chloroform (9:1) |
0.33 |
|
SM-4j |
4’- methoxy benzaldehyde |
C24H19ClN2O3S |
450.1 |
177 |
70 |
Methanol: Chloroform (9:1) |
0.75 |
|
SM-4k |
4’ –dimethyl amino benzaldehyde |
C25H22ClN3O2S |
463.1 |
192 |
55 |
Methanol: Chloroform (9:1) |
0.59 |
|
SM-4l |
4’ –methyl benzaldehyde |
C25H22ClN3O2S |
435.0 |
183 |
48 |
Methanol: Chloroform (9:1) |
0.66 |
Table-3 Spectral data of 2-amino-4-(4-chlorophenyl)-N-(3-furan-2-ylmethyl carboxamido) thiophene.(SM-4)
|
Comp Code |
λ max.(nm) |
IR |
1 H NMR |
|
SM-4 |
159 |
3303.46 cm-1(NH stretch of amide);3092.12 cm-1(Ar-CH );2776.9 cm-1(Ali-CH);1672.9 cm-1(C=O of amide);1620.30(-NH bend); 1524.65 (Ar C=C);1648.61 (HC=N);1148.14 cm-1(C-O of furan);871.09 (C-N);751.89 (C-S);721.85 (C-Cl) |
8.0(s,1H of CONH-)7.3-7.5(m,2H of aromatic H)7.2-7.4(m,2H of aromatic )7.1(d,1H of furfuryl ring)6.4(s,1H of thiophene)6.2(d,2H of furfuryl ring) 4.1(d,2H of –CH2of furfuryl ring 5.5(s,2H of NH2) |
Antimicrobial studies
All the synthesized compounds were screened for their antibacterial and antifungal activity by agar diffusion method 12 at a conc of 50µg/ml against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Klebsiella pneumonia, Aspergillus niger and Candida albicans .After 24 hours of drug addition, zone of inhibition was measured and recorded. Ampicillin, Norfloxacin and Mecanazole nitrate at 50µg/ml were used as standards in the experiment
RESULTS:
From the antibacterial activity results it was observed that both electron donating and electron withdrawing groups on the aldehydic phenyl ring of the compounds influenced the activity. Among the drugs tested for antimicrobial activities Table 5, Table 6 showed that compounds SM-4a, SM-4e, SM-4f, SM-4g, SM-4i exhibited potent activity by showing zone of inhibition ranging from 15mm-23mm.All these drugs showed potent activity against Staphylococcus aureus with high zone of inhibition. All other drug showed drugs showed moderate inhibitory properties against the test organism. Against Candida albicans none of the test drugs showed significant activity. Standard drugs, Ampicillin, Norfloxacin and Mecanazole nitrate exhibited potent inhibitory properties against all the test organism.
DISCUSSION:
From the IR, 1H, NMR and mass spectrum obtained, characterization of data has been done and given in table 1, 2, 3 and 4. The IR spectrum of 2-amino-4-(4-chlorophenyl)-N-(3-furan-2-ylmethylcarboxamido)thiophene. (SM-4) shows NH2 peak at3306.46 cm-1.The NMR spectrum shows a broad peak at δ =5.5 of NH2.
The IR spectra of all the Schiff bases shows the disappearance of NH2 peak and the appearance of –N=CH (Imine) peak at the range of 1640-1680 cm-1 which clearly suggest the formation of expected compounds. The NMR spectra of the compounds SM-4b,SM-4c,SM-4e,SM-4g and SM-4l shows sharp singlet peak at the range of δ =8.2-8.7 of –N=CH (Imine) which also further confirms the formation of the compounds of the series. The compounds SM-4b, SM-4c and SM-4e, SM-4g, SM-4l were also confirmed by Mass spectrum.
Table-4 Spectral data of 2-[(substituted benzylidene) amino] 4-(4-chlorophenyl)-N-(3-furan-2-ylmethyl carboxamido) thiophenes.(SM-4a-4l)
|
X |
λ max. (nm) |
IR |
1 H NMR |
Mass |
|
3’4’5’–trimethoxy benzaldehyde |
275 |
3393.41 cm-1(NH stretch of amide);3100.21cm-1(Ar-CH );2779.5 cm-1(Ali-CH);1670.0 cm-1(C=O of amide);1621.21(-NH bend); 1525.45 (Ar C=C);1647.01 (HC=N); 1257.95 (Ar C-O of OCH3);1148.41 cm-1(C-O of furan);870.00 (C-N);752.88 (C-S);721.06 (C-Cl) |
|
|
|
3’4’–dimethoxy benzaldehyde |
271 |
3396.32 cm-1(NH stretch of amide);3165.29cm-1(Ar-CH );2780.32 cm-1(Ali-CH);1674.96cm-1(C=O of amide);1622.22(-NH bend); 1524.44 (Ar C=C);1646.00 (HC=N); 1251.76 (Ar C-O of OCH3);1142.65 cm-1(C-O of furan);870.00 (C-N);750.34 (C-S);724.32(C-Cl) |
8.2(s,2H 1H of CONH- ,1H of N=CH)7.4-7.6(m,4H of aromatic H)7.3-7.5(m,3H of aromatic )7.1(d,1H of furfuryl ring)6.5(s,1H of thiophene)6.0(d,2H of furfuryl ring) 3.5(s,6H of –OCH3)4.1(d,2H of –CH2of furfuryl ring |
480 |
|
2’-nitro benzaldehyde |
249 |
3389.30 cm-1(NH stretch of amide);3159.78cm-1(Ar-CH );2789.01 cm-1(Ali-CH);1677.69cm-1(C=O of amide);1654.98(-NH bend); 1521.32 (Ar C=C);1647.43 (HC=N);1381.34 (N-O of NO2);1141.62 cm-1(C-O of furan);875.52 (C-N);754.33 (C-S);724.22(C-Cl) |
8.6(s,2H 1H of CONH-,1H of N=CH) 8.0(1H of aromatic H) 7.4-7.6(m,3H of aromatic H) 7.7-7.8(m,4H of aromatic H) 7.1(d,1H of furfuryl ring) 6.5(s,1H of thiophene)6.0(d,2H of furfuryl ring)4.1(d,2H of –CH2 of furfuryl ring) |
423 |
|
3’-nitro benzaldehyde |
263 |
3370.40 cm-1(NH stretch of amide);3161.77cm-1(Ar-CH );2791.31 cm-1(Ali-CH);1640.21cm-1(C=O of amide);1649.47(-NH bend); 1522.89 (Ar C=C);1647.40 (HC=N);1379.21 (N-O of NO2);1142.60 cm-1(C-O of furan);875.65 (C-N);752.21 (C-S);743.31(C-Cl) |
|
|
|
2’ -chloro benzaldehyde |
269 |
3350.45 cm-1(NH stretch of amide);3201.32cm-1(Ar-CH );2798.36 cm-1(Ali-CH);1642.21cm-1(C=O of amide);1650.34(-NH bend); 1530.84 (Ar C=C);1646.32 (HC=N);1148.43 cm-1(C-O of furan);877.21 (C-N);749.61 (C-S);747.62(C-Cl) |
8.5(s,2H 1H of CONH- ,1H of N=CH)7.5-7.7((m,4H aromatic H) 7.8-7.9(m,4H aromatic H) 7.1(d,1H of furfuryl ring) 6.9 (s,1H of thiophene)6.1(d,2H of furfuryl ring) 4.3(d,2H of –CH2 of furfuryl ring) |
455 |
|
4’-chloro benzaldehyde |
245 |
3345.45 cm-1(NH stretch of amide);3279.43cm-1(Ar-CH);2794.33cm-1(Ali-CH);1650.09cm-1(C=O of amide);1665.06(-NH bend); 1521.62(Ar C=C);1644.32 (HC=N);1146.03 cm-1(C-O of furan);879.12 (C-N);750.03 (C-S);749.32(C-Cl) |
|
|
|
4’-hydroxy benzaldehyde |
250 |
3354 cm-1 (OH); 3342.45 cm-1(NH stretch of amide);3200.21cm-1(Ar-CH );2766.23 cm-1(Ali-CH);1640.20cm-1(C=O of amide);1643.32(-NH bend); 1524.67(ArC=C);1642.65(HC=N);1148.43 cm-1(C-O of furan);877.21 (C-N);744.61 (C-S);748.22(C-Cl) |
8.3(s,2H 1H of CONH- ,1H of N=CH)7.3-7.5((m,4H aromatic H) 7.6-7.9(m,4H aromatic H) 7.0(d,1H of furfuryl ring) 6.6 (s,1H of thiophene)6.2(d,2H of furfuryl ring) 5.2(s,1Hof OH) 4.2(d,2H of –CH2 of furfuryl ring) |
436 |
|
4’ –hydroxy 3-methoxy benzaldehyde |
220 |
3400.07 cm-1 (OH); 3343.51 cm-1(NH stretch of amide);3165.29cm-1(Ar-CH );2780.32 cm-1(Ali-CH);1674.96cm-1(C=O of amide);1622.22(-NH bend); 1523.99 (Ar C=C);1654.16 (HC=N); 1255.77 (Ar C-O of OCH3);1144.55 cm-1(C-O of furan);875.01 (C-N);757.36 (C-S);729.32(C-Cl) |
|
|
|
2’ -hydroxy benzaldehyde |
237 |
3360.03 cm-1 (OH); 3347.44 cm-1(NH stretch of amide);3276.27cm-1(Ar-CH );2769.27 cm-1(Ali-CH);1651.23cm-1(C=O of amide);1639.27(-NH bend); 1532.23(ArC=C);1651.05(HC=N);1154.34 cm-1(C-O of furan);878.22 (C-N);745.69 (C-S);750.27(C-Cl) |
|
|
|
4’–methoxy benzaldehyde |
274 |
3400.26 cm-1(NH stretch of amide);3208.64cm-1(Ar-CH );2780.32 cm-1(Ali-CH);1674.96cm-1(C=O of amide);1622.22(-NH bend); 1524.44 (Ar C=C);1646.00 (HC=N); 1251.76 (Ar C-O of OCH3);1142.65 cm-1(C-O of furan);870.00 (C-N);750.34 (C-S);724.32(C-Cl) |
|
|
|
4’–dimethyl amino benzaldehyde |
236 |
3396.32 cm-1(NH stretch of amide); 3165.29cm-1(Ar-CH); 2780.32 cm-1(Ali-CH); 2959.13 (CH of CH3). 1674.96cm-1(C=O of amide);1622.22(-NH bend); 1524.44 (Ar C=C);1646.00 (HC=N); 1251.76 (Ar C-O of OCH3);1142.65 cm-1(C-O of furan);870.00 (C-N);750.34 (C-S);724.32(C-Cl) |
|
|
|
4’ –methyl benzaldehyde |
227 |
3246.01 cm-1 (NH); 3043.00 cm-1 (Ar-CH,Str); 2876.06cm-1(Ali-CH); 2948.13 (CH of CH3). 1622.21 cm-1 (C-N, imine, Str);(C=C,Ar, Str);1321.21 cm-1 (C=N); 1609.06cm-1 (C=O);741cm-1 (C-Cl);776.03 cm-1 (C-S) |
8.1(s,2H 1H of CONH- ,1H of N=CH)7.3-7.5((m,4H aromatic H) 7.6-7.7(m,4H aromatic H) 7.1(d,1H of furfuryl ring) 6.8 (s,1H of thiophene)6.0(d,2H of furfuryl ring) 4.2(d,2H of –CH2 of furfuryl ring) 2.1(s,3H of CH3) |
435 |
Table-5 Antimicrobial activity of 2-amino-4-(4-chlorophenyl)-N-(3-furan-2-ylmethyl carboxamido) thiophene. (SM-4)
|
Comp Code |
S.aureus |
B.subtilus |
E.coli |
K.pneumonia |
A.niger |
C.albicans |
|
SM-4 |
16 |
14 |
13 |
13 |
16 |
-- |
|
Ampicillin |
23 |
17 |
23 |
17 |
-- |
-- |
|
Norfloxacin |
24 |
27 |
26 |
27 |
-- |
-- |
|
Miconazole |
-- |
-- |
-- |
-- |
30 |
27 |
Table -6 Antimicrobial activity of 2-[(substituted benzylidene) amino] 4-(4-chlorophenyl)-N-(3-furan-2-ylmethyl carboxamido) thiophenes.(SM-4a-4l)
|
Comp Code |
S.aureus |
B.subtilus |
E.coli |
K.pneumonia |
A.niger |
C.albicans |
|
3’4’5’–trimethoxy benzaldehyde |
21 |
18 |
-- |
14 |
14 |
-- |
|
3’4’–dimethoxy benzaldehyde |
16 |
15 |
-- |
14 |
15 |
-- |
|
2’-nitro benzaldehyde |
14 |
13 |
11 |
10 |
13 |
-- |
|
3’-nitro benzaldehyde |
13 |
11 |
10 |
10 |
12 |
-- |
|
2’ chloro benzaldehyde |
22 |
19 |
19 |
18 |
18 |
10 |
|
4’-chloro benzaldehyde |
23 |
19 |
20 |
18 |
19 |
11 |
|
4’-hydroxy benzaldehyde |
22 |
18 |
17 |
18 |
17 |
10 |
|
4’-hydroxy 3’- methoxy benzaldehyde |
20 |
16 |
19 |
16 |
18 |
09 |
|
2’ –hydroxy benzaldehyde |
22 |
16 |
19 |
17 |
18 |
09 |
|
4’ –methoxy benzaldehyde |
14 |
14 |
15 |
18 |
18 |
08 |
|
4’ –dimethyl amino benzaldehyde |
12 |
13 |
14 |
-- |
15 |
-- |
|
4’ –methyl benzaldehyde |
16 |
15 |
14 |
14 |
13 |
-- |
|
Ampicillin |
22 |
18 |
24 |
18 |
-- |
-- |
|
Norfloxacin |
33 |
28 |
26 |
28 |
-- |
-- |
|
Miconazole |
-- |
-- |
-- |
-- |
30 |
27 |
ACKNOWLEDGEMENTS:
The authors are thankful to Management, PES college of Pharmacy for providing necessary facilities.
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Received on 04.12.2012 Modified on 14.12.2012
Accepted on 20.12.2012 © AJRC All right reserved
Asian J. Research Chem. 6(1): January 2013; Page 24-28