Synthesis of 5-benzylidene-3-(3-fluoro-4-yl-morpholin-4-yl-phenylimino)- thiazolidin-4-one derivatives catalyzed by [BmIm]OH and their anti-microbial activity

Article abstract of DOI:10.1016/j.cclet.2011.03.002

A series of novel 5-benzylidene-3-(3-fluoro-4-yl-morpholin-4-yl- phenylimino)thiazolidin-4-one derivatives were synthesized using [bmIm]OH as a catalyst and were tested for their antibacterial and antifungal activities. These compounds showed moderate in

Full text of DOI:10.1016/j.cclet.2011.03.002

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 883–886
www.elsevier.com/locate/cclet
Synthesis of 5-benzylidene-3-(3-fluoro-4-yl-morpholin-4-yl-
phenylimino)-thiazolidin-4-one derivatives catalyzed
by [BmIm]OH and their anti-microbial activity
a
a
b
Sudhakar G. Patil a, , Rahul R. Bagul , Mangesh S. Swami , Nandini Kotharkar ,
*
Kalpana Darade b
a Organic Chemistry Research Laboratory, Maharashtra Udaygiri Mahavidyalay, Udgir 413517, Maharashtra, India
b G. H. Raisoni Institute Interdisciplinary Sciences Wagholi, Pune 411 001, India
Received 8 October 2010
Available online 18 May 2011
Abstract
A series of novel 5-benzylidene-3-(3-fluoro-4-yl-morpholin-4-yl-phenylimino)thiazolidin-4-one derivatives were synthesized
using [bmIm]OH as a catalyst and were tested for their antibacterial and antifungal activities. These compounds showed moderate in
vitro activities against the microorganisms tested.
# 2011 Sudhakar G. Patil. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Basic ionic liquid; [bmIm]OH; Antimicrobials; Anti-bacterial; Anti-fungal; Iminothizolidin-4-one
4-Phenyl-morpholine derivatives are reported to possess antimicrobial [1,2] and antiinflammatory [3–5] activities.
4-Thiazolidinone derivatives are also known to possess antibacterial [6–10], antifungal [11–13], antiviral [14] and
antituberculosis [15–17] properties. Linezolide (PNU-10766, commercially available antimicrobial drug) possess
4-(2-flourophenyl) morpholine moiety, these observations led to the conception that 5-benzylidene derivatives of
3-ethyl-2-(3-fluoro-4-morpholin-4-yl-phenylimino)-thiazolidin-4-one would possess potential anti-microbial proper-
ties (Fig. 1). Several methods were reported in the literature for the preparation of thiazolidinone derivatives [18] and
iminothiazolidin-4-one derivatives [19].
In the present study a novel series of 5-benzylidene-3-ethyl-2-(3-fluoro-4-morpholin-4-yl-phenylimino)-
thiazolidin-4-ones were synthesized. The key steps of formation of iminothiazolidinone (5) and its Knovengel
condensation with aryl aldehyde to 5-benzylidene-3-(3-fluoro-4-yl-morpholin-4-yl-phenylimino)-thiazolidin-4-one
(6) were carried using basic ionic liquid [bmIm]OH [20] as a catalyst as well as solvent, with excellent yields.
Our synthetic strategy for thiazolidinone derivatives is illustrated in Scheme 1. The synthesis starts with reaction of
2,4-difluoro-1-nitrobenzene (1) with morpholine and potassium carbonate in dimethylformamide at 80 8C afforded
4-(3-fluoro-4-nitrophenyl)morpholine (2) which on catalytic reduction using H2/Pd/C in methanol afforded 2-fluoro-
4-morpholin-4-yl-phenylamine (3) [21]. The phenylamine (3) was futher treated with ethylisothiocynate in ethanol at
* Corresponding author.
E-mail address: patil.sudhakar261@gmail.com (S.G. Patil).
1001-8417/$ – see front matter # 2011 Sudhakar G. Patil. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.03.002

8[()TD$FIG] 84
S.G. Patil et al. / Chinese Chemical Letters 22 (2011) 883–886
O
F
F
O
N
S
O
CH3
H
N
O
O
N
N
N
N
R
O
PNU-10766
6
Fig. 1. Structure of PNU-10766 and 5-benzylidene-3-ethyl-2-(3-fluoro-4-morpholin-4-yl-phenylimino)-thiazolidin-4-one 6.
80 8C afforded 1-ethyl-3-(2-fluoro-4-morpholin-4-yl-phenyl)-thiourea (4) [22]. 1-Ethyl-3-(2-fluoro-4-morpholin-4-
yl-phenyl)thiourea (4) was treated with ethylbromoacetate in basic ionic liquid [bmIm]OH at room temperature, the
key intermediate 3-ethyl-2-(2-fluoro-4-morpholin-4-yl-phenylimino)thiazolidin-4-one (5) was isolated with 95%
yield [23]. 1H NMR spectrum of compound 5 shows a singlet at 4.02 ppm for two protons is characteristic value of C-5
protons of the iminothiazolidinone nucleus. The strong absorption bands at 1708 cmÀ1 and at 1620 cmÀ1 confirms the
presence of C O and C N functional groups respectively and hence confirms the formation of iminothiazolidinone
compound 5. This clearly indicates that basic ionic liquid [bmIm]OH catalyzes cyclization of thiourea with ethyl
bromoacetate which is a key step in the current synthesis.
This key intermediate iminothiazolidin-4-one (5) on Knovengel condensation with different substituted aryl
aldehydes in [bmIm]OH afforded the 5-benzylidene-3-(3-fluoro-4-yl-morpholin-4-yl-phenylimino)thiazolidin-4-one
6(a–p) in excellent yields (Table 1) [24]. The ionic liquid used in the reaction was recovered from aqueous layer and
washed with diethyl ether to remove any organic impurities and dried under vacuum to get the pure ionic liquid and
was reused for the above reactions. We have tested reusability of ionic liquid for compound (6j), upon use of three
times, showed no loss of its activity and does not vary yield of final product. All these compounds were characterized
1
by IR, H NMR and MS [26]. These compounds were furter used for the biological studies.
The antimicrobial activity of the compuond was assayed by antimicrobial susceptibilty test [25]. 100 mL of 24 h
growth of each microorganism was spread on the surface of nutrient agar for bacteria (Mac Conkey’s agar for
Escherichia coli) and potato dextrose agar for fungi, in Petri plates. 50 mL compound at the concentration of 100 mg/
mL in DMSO saturated on discs of 6 mm diameter were kept on agar surface. The plates refrigerated for two hours to
allow prediffusion of the compound from the discs in to the seeded agar layer and then incubated at 37 8C for 24 h for
bacteria and 28 8C for 48 h for fungi. Zones of inhibition were measured in mm and size of the disc was subtracted
from the zone size to measured final activity. DMSO saturated discs served as solvent control or negative control and
Streptomycin saturated discs (30 mg) for bacteria and Nystatin (30 mg) for fungi as a reference or positive control.
The newly synthesized compounds were tested to evaluate their antibacterial and antifungal activity. All these
compounds were found to exhibit moderate antibacterial and antifungal activity against different species of bacteria
and fungi. From the activity data (Table 1) it was observed that among all the compounds tested, compound 6o shows
good activity against all the tested bacteria and fungi. Among all tested bacteria and fungi compound 6o showed good
[()TD$FIG]
Scheme 1. Synthetic scheme for compound 6(a–p).

S.G. Patil et al. / Chinese Chemical Letters 22 (2011) 883–886
885
Table 1
Yield and antimicrobial activitya of benzilidene derivatives (6a–6p).
Aldehyde
Yield (%)b
Zone of inhibition (mm)c
Bactria
Fungi
Staphylococous
aureus
Bacillus
Escherichia coli
Aspergillus
niger
Rhizopus otyzae
subtillis
NCLM-2809
NCLM-1299
NCLM-2602
NCLM-2458
NCLM-617
Benzaldehyde
6a (90)
6b (93)
6c (92)
6d (89)
6e (94)
6f (91)
6g (90)
6h (88)
6i (90)
6j (95)
6k (92)
6l (87)
6m(88)
6n (90)
6o (94)
6p (92)
3
1
2
3
3
2
2
3
2
1
3
2
2
3
5
2
2
3
3
2
2
3
1
2
2
3
2
1
2
2
8
2
3
2
2
1
3
2
1
2
1
2
3
2
2
3
5
3
2
3
1
2
2
3
1
2
1
2
3
2
2
3
4
4
1
2
1
2
3
2
2
1
2
3
1
2
2
3
4
3
4-Hydroxy-benzaldehyde
3-Hydroxy-benzaldehyde
2-Hydroxy-benzaldehyde
4-Fluorobenzaldehyde
3-Fluorobenzaldehyde
2,4-Difluoro-benzaldehyde
4-Cyanobenzaldehyde
4-Nitrobenzaldehyde
4-Isopropyl-benzaldehyde
4-Methoxy-benzaldehyde
3-Nitrobenzaldehyde
4-Bromobenzaldehyde
4-Hydroxy-3-methoxy benzaldehyde
2,4,6-Trimethoxy-benzaldehyde
1H-Indol-3-carboxaldehyde
Standard
Antibioticd
–
10
8
9
8
9
a
These results are average results of four experiments.
Isolated yields of 6 after 3 h.
These compounds were used at concentration of 100 mg/mL.
b
c
d
Streptomycin for bacteria and Nystain for fungi were used at concentration of 30 mg.
activity against Staphylocococous aureus (inhibition 5 mm, standard showed 10 mm) and Bacillus subtillis (inhibition
8 mm, standard showed 8 mm). Among the other compounds 6a, 6e, 6k and 6n shown moderate activity against
Escherichia coli and the compounds 6b, 6c, 6f, 6j and 6p showed moderate activity against Bacillus subtillis bacteria.
Compounds 6n and 6p showed moderate activity against Aspergillus Niger and Rhizopus Otyzae fungi.
In conclusion, we have synthesised a series of novel thiazolidinone derivatives using [bmIm]OH as a catalyst as
well as solvent for the key step of formation of iminothiazolidinone and its Knovengel condensation with aromatic
aldehydes. These compounds have been screened for potential antibacterial and antifungal activities. The results from
our biological activity studies showed that compound 6o having 2,4,6-trimethoxy group on benzilidene moiety shows
good activity against all tested bacteria and fungi.
Acknowledgments
We are gratefully acknowledged DST (No. SR/FTP/CS-114/2007) New Delhi, India for financial assistance. M.S.S.
thanks to DST for scholarship.
References
[1] R.S. Varma, R. Prakash, N.M. Khan, et al. Indian Drugs 23 (1983) 345.
[2] J.B. Hester, E.G. Nidy, S.C. Perricone, et al. PCT Int. Appl. (2001) (WO00144188).
[3] V.S. Misra, S. Singh, R. Agarwal, et al. J. Chem. Soc. Pak. 3 (1981) 209.
[4] M. Verma, V. Sharma, A. Saxena, et al. Pharmacol. Res. Commun. 16 (1984) 9.
[5] R. Agarwal, C. Agarwal, S. Singh, et al. J. Chem. Soc. Pak. 6 (1984) 209.
¨
[6] O. Ates¸, A. Kocabalkanlı, G. Sanıs¸-Otu¨k, et al. Arzneim.-Forsch./Drug Res. 47 (1997) 1134.
¨
¨
[7] O. Ates¸, H. Altıntas¸, G. Otu¨k, Arzneim.-Forsch./Drug Res. 50 (2000) 569.
¨

886
S.G. Patil et al. / Chinese Chemical Letters 22 (2011) 883–886
¨
¨
[8] A. Kocabalkanlı, O. Ates¸, G. Otu¨k, Arch. Pharm. Med. Chem. 334 (2001) 35.
[9] S¸. Ku¨c¸u¨kgu¨zel, E. Oruc¸, E. Rollas, et al. Eur. J. Med. Chem. 37 (2002) 197.
[10] C.G. Bonde, N.J. Gaikwad, Bioorg. Med. Chem. 12 (2004) 2151.
[11] N. Cesur, Z. Cesur, N. Ergenc¸, et al. Arch. Pharm. (Weinheim) 327 (1994) 271.
˙
[12] N. Karali, E. Ilhan, A. Gu¨rsoy, M. Kiraz, Farmaco 53 (1998) 346.
[13] H.T.Y. Fahmy, Boll. Chim. Farmaco 140 (2001) 422.
[14] M. Barreca, A. Chimirri, L. Luca, et al. Bioorg. Med. Chem. Lett. 11 (2001) 1793.
[15] L. Bukowski, M. Janowiec, Z. Zwolska-Kwiek, et al. Pharmazie 53 (1998) 373.
[16] N. Ulusoy, Arzneim.-Forsch./Drug Res. 52 (2002) 565.
[17] K. Babaoglu, M. Page, V. Jones, et al. Bioorg. Med. Chem. Lett. 13 (2003) 3227.
[18] (a) J.F. Dubreuil, J.P. Bazureau, Tetrahedron 59 (2003) 121;
(b) A. Verma, S.K. Saraf, Eur. J. Med. Chem. 43 (2008) 897;
(c) T. Srivastava, W. Haq, S.B. Katti, Tetrahedron 58 (2002) 7619;
(d) R.K. Rawal, T. Srivastava, W. Haq, S.B. Katti, J. Chem. Res. (2004) 368.
[19] (a) P. Vicini, A. Geronikaki, K. Anastasia, et al. Bioorg. Med. Chem. 14 (2006) 3859;
(b) R. Ottana, R. Maccari, M.L. Barreca, et al. Bioorg. Med. Chem. 13 (2005) 4243;
(c) J. Fraga-Dubreuil, J.P. Bazureau, Tetrahedron 59 (2003) 6121;
(d) A. Dandia, R. Singh, S. Khaturia, et al. Bioorg. Med. Chem. 14 (2006) 2409;
(e) C. Holmes, J.P. Chinn, G.C. Look, et al. J. Org. Chem. 60 (1995) 7328.
[20] B.C. Ranu, R. Jana, Eur. J. Org. Chem. (2006) 3767.
[21] S.J. Brickner, D.K. Hutchinson, M.R. Barbachyn, et al. J. Med. Chem. 39 (1996) 673.
[22] A. Saeed, M. Parvez, Cent. Eur. J. Chem. 3 (2005) 780.
[23] The solution 2-fluoro-4-morpholin-4-yl-phenylamine (3) (1 mmol) and ethyl bromoacetate (1.1 mmol) in [bmIm]OH (2 mmol) was stirred at
rt. After 6 h cold water was added and extracted with ethyl acetate (3Â 10 mL), washed with brine and dried over anhydrous sodium sulfate and
concentrated. The crude product was purified by silica gel column chromatography using petroleum ether: ethyl acetate (20:1) eluent to get
pure iminothiazolidin-4-one (5). Aqueous layer was re-extracted with ether (3Â 10 mL) to remove organic impurities and dried under vacuum
at 90 8C to get pure ionic liquid.
[24] A mixture iminothiazolidin-4-one (5) (1 mmol) and aldehyde (1.1 mmol) in [bmIm]OH (2 mmol) was stirred at rt. After 3 h cold water was
added and residue was filtered dried and recrystalized from hot ethanol to get pure 5-benzylidene-3-(3-fluoro-4-yl-morpholin-4-yl-
phenylimino)-thiazolidin-4-one (6). Aqueous layer was re-extracted with ether (3Â 10 mL) to remove organic impurities and dried under
vacuum at 90 8C to get pure ionic liquid.
[25] C. Kaneko, S. Katagiri, Japan Kokai Tokkyo Koho JP 62 (1988) 264.
1
[26] Analytical data: 3-Ethyl-2-(3-fluoro-4-morpholin-4-yl-phenylimino)thiazolidin-4-one (5): Reddish solid; H NMR (DMSO-d6, 200 MHz): d
1.16 (t, 3H, J = 6.9 Hz), 2.97 (t, 4H, J = 3.4 Hz), 3.72–3.79 (m, 6H), 4.02 (s, 2H), 6.70–6.82 (m, 2H), 6.97–7.06 (m, 1H); MS (m/z): 324.5
[M++1]; IR (KBr): 1709, 1630. (5E)-3-Ethyl-2-(3-fluoro-4-morpholinophenylimino)-5-(4-methoxybenzylidene)thiazolidin-4-one (6k): Yellow
solid; mp: 138–140 8C; 1H NMR (CDCl3, 400 MHz): d 1.34 (t, 3H, J = 7.0 Hz), 3.10–3.14 (m, 4H), 3.83 (s, 3H), 3.90–4.00 (m, 4H), 4.03 (q,
2H, J = 7.0 Hz), 6.75–6.82 (m, 2H), 6.94 (d, 2H, J = 8.8 Hz), 6.98–7.10 (m, 1H), 7.41 (d, 2H, J = 8.8 Hz), 7.71 (s, 1H); MS (m/z) 442.5 [M++1];
IR (KBr): 2968, 2852, 2821, 1705, 1637, 1504, 1377, 1338, 1268, 1116, 1043, 923. (5E)-3-Ethyl-2-(3-fluoro-4-morpholinophenylimino)-5-(4-
hydroxy-3-methoxybenzylidene)thiazolidin-4-one (6n): Yellow solid; mp: 176–178 8C; 1H NMR (CDCl3, 200 MHz): (1.34 (t, 3H, J = 7.0 Hz),
1.59 (bs, 1H, exchangeable with D2O), 3.11 (t, 4H, J = 4.4 Hz), 3.83 (s, 3H), 3.89 (t, 4H, J = 4.4 Hz), 4.03 (q, 2H, J = 7.0 Hz), 6.74–6.82 (m,
2H), 6.90–7.00 (m, 3H), 7.41 (d, 1H, J = 8.7 Hz), 7.70 (s, 1H); MS (m/z): 458.5 [M++1]; IR (KBr): 3541, 2969, 2854, 2824, 1710, 1639, 1509,
1380, 1339, 1270, 1115, 1043, 923. (5E)-3-Ethyl-2-(3-fluoro-4-morpholinophenylimino)-5-(2, 4, 6-trimethoxybenzylidene)thiazolidin-4-one
(6o): Yellow solid; mp: 133–135 8C; 1H NMR (CDCl3, 200 MHz): d 1.34 (t, 3H, J = 7.0 Hz), 3.10 (t, 4H, J = 4.6 Hz), 3.89 (s, 9H), 3.89 (t, 4H,
J = 4.6 Hz), 4.02 (q, 4H, J = 7.0 Hz), 6.07 (s, 2H), 6.72–6.94 (m, 3H), 7.98 (s, 1H); MS (m/z): 502.5 [M++1]; IR (KBr): 2954, 2902, 2853, 2820,
2360, 2333, 1655, 1640, 1620, 1550,1369, 1118, 915. (5E)-5-((1H-indol-3-yl) methylene)-3-ethyl-2-(3-fluoro-4-morpholinophenylimino)thia-
zolidin-4-one (6p): Yellow solid; mp: 137–139 8C; 1H NMR (CDCl3, 400 MHz): d 1.36 (t, 3H, J = 7.0 Hz), 3.11 (t, 4H, J = 4.4 Hz), 3.90 (t, 4H,
J = 4.4 Hz), 4.05 (q, 2H, J = 7.0 Hz), 6.78–6.83 (m, 2H), 6.96 (t, 1H, J = 9.0 Hz), 7.28–7.32 (m, 2H), 7.42 (d, 1H, J = 7.6 Hz), 7.44 (m, d, 1H,
J = 2.8 Hz), 7.85 (d, 1H, J = 7.6 Hz), 8.11 (s, 1H), 8.62 (bs, 1H, exchangeable with D2O); MS (m/z): 451.5 [M++1]; IR (KBr): 3403, 3174, 2955,
2891, 2837, 2700, 2360, 2251, 1701, 1633, 1602, 1114, 923.