Green synthesis of some new (substituted fluorobenzoylimino)-3-aryl-4- methyl-1,3-thiazolines

Article abstract of DOI:10.1080/00397910903004381

A series of 2-, 3-, and 4-substituted (fluorobenzoylimino)-3-aryl-4-methyl- 1,3-thiazolines (2a-j) were synthesized in good yields by the base-catalyzed cyclization of corresponding 1-(fluorobenzoyl)-3-(fluorophenyl)thioureas (1a-j) with-bromoacetone in water. Compared to the reactions in conventional nonaqueous solvents under inert anhydrous conditions, the aqueous medium provides a much cleaner, more efficient, and simpler method for synthesis. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903004381

This article was downloaded by: [Fordham University]
On: 02 December 2012, At: 05:46
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Green Synthesis of Some New
(Substituted Fluorobenzoylimino)-3-
aryl-4-methyl-1,3-thiazolines
Aamer Saeed a & Uzma Shaheen a
a Department of Chemistry, Quaid-I-Azam University, Islamabad,
Pakistan
Version of record first published: 03 Feb 2010.
To cite this article: Aamer Saeed & Uzma Shaheen (2010): Green Synthesis of Some New (Substituted
Fluorobenzoylimino)-3-aryl-4-methyl-1,3-thiazolines, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 40:4, 564-569
To link to this article: http://dx.doi.org/10.1080/00397910903004381
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 40: 564–569, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903004381
GREEN SYNTHESIS OF SOME NEW
(SUBSTITUTED FLUOROBENZOYLIMINO)-3-ARYL-4-
METHYL-1,3-THIAZOLINES
Aamer Saeed and Uzma Shaheen
Department of Chemistry, Quaid-I-Azam University, Islamabad, Pakistan
A series of 2-, 3-, and 4-substituted (fluorobenzoylimino)-3-aryl-4-methyl-1,3-thiazolines
(2a–j) were synthesized in good yields by the base-catalyzed cyclization of corresponding
1-(fluorobenzoyl)-3-(fluorophenyl)thioureas (1a–j) with a-bromoacetone in water.
Compared to the reactions in conventional nonaqueous solvents under inert anhydrous
conditions, the aqueous medium provides a much cleaner, more efficient, and simpler
method for synthesis.
Keywords: Fluorobenzoylimino-1,3-thiazolines; green synthesis
INTRODUCTION
There has been considerable interest in recent years in carrying out organic
synthesis in unconventional polar solvents such as water. Although water is the most
inexpensive, safe, and nonhazardous green solvent, its use as a medium for organic
reactions has been limited in spite of the fact that many biochemical processes in
nature take place in the presence of water molecules. Because of its polarity, many
organic substrates appear to be insoluble in water, giving suspensions, and it was
considered that the presence of water would result in slow reaction rates and poor
yields of the products. In fact, its presence was strictly avoided by drying the
substrates and using anhydrous solvents. Later on, after the identification of the
hydrophobic effect, solvation, and stereochemical effects in water, there was an
excited boost in attempting organic reactions in water. It is suggested that reactions
‘‘on water’’ actually go on through small amounts of dissolved solutes. It occurs at
the aqueous–organic interface, therefore vigorous stirring of the reaction mixture is
considered to be helpful. The ultimate goal is to carry out organic reactions in vitro
under mild conditions even in the absence of enzyme catalysis.[1–4] 2-Imino-1,3-
thiazoline nucleus is found in a variety of biologically active natural products and
find extensive applications in medicinal chemistry. 2-Thiazolylimino-5-arylidene-
4-thiazolidinones show noticeable antimicrobial activity against bacteria, yeasts,
and mold.[5] 3-Substituted 2-(cyanoimino)thiazolidines can be used in agriculture
Received February 26, 2009.
Address correspondence to Aamer Saeed, Department of Chemistry, Quaid-I-Azam University,
Islamabad 45320, Pakistan. E-mail: aamersaeed@yahoo.com
564

FLUOROBENZOYLIMINO-3-ARYLTHIAZOLINES
565
because of their neonicotinoid insecticidal activity.[6] 3-Substituted thiazolidines
show radioprotective properties against c-radiations.[7] A quantitative structural–
activity relationship (QSAR) study for fungicidal activities of 2-imino-1,3-thiazoline
derivatives against rice blast fungus Pyricularia oryzae[8] has revealed their potent use
as fungicides. KHG22394, a 2-imino-1,3-thiazoline derivative, significantly inhibits
melanin production in a dose-dependant manner, thus acting as a skin whitening
agent,[9] and pifithrin-a, another imino thiazoline, is a reversible inhibitor of p53-
mediated apoptosis and p53-dependent gene transcription.[10] Amidine derivatives
synthesized by condensation of 2-cyanopyridine with various 3,4-diaryl-2-imino-
4-thiazolines exhibited good anti-inflammatory activity and analgesic activity.[11]
3-Alkyl-3-H-thiazoline derivative PS 028, a GP IIb=IIIa receptor antagonist, is a
lead compound for an orally active potent platelet aggregation inhibitor.[12]
Acridinyl-thiazoline derivatives exhibit moderate CDK1 inhibitory activity.[13]
Sydnonyl-substituted thiazoline derivatives exhibit potent DPPH radical scavenging
activity.[14] 2-Acylimino-1,3-thiazolines show bleaching herbicidal activity against
upland weeds and selectivity against crops.[15] Keeping in view these biological
activities and synthetic significance, herein we describe an efficient and clean syn-
thesis of some new (substituted fluorobenzoylimino)-3-aryl-4-methyl-1,3-thiazolines
in aqueous medium.
RESULTS AND DISCUSSION
The cyclocondensation of 1-aroyl-3-arylthioureas with a-halocarbonyl
compounds is classically achieved in the presence of bromine in a basic medium
and rigorously dry solvents such as acetone, dichloromethane, or acetonitrile under
an inert atmosphere.[16–19] Despite these conventional, nonaqueous media, such con-
densations require longer reaction times (3–5 h reflux) and give comparatively lesser
yields. Reaction in water not only shortens the reaction times but also increases pro-
duct purities and yields. The precursors 1-(fluorobenzoyl)-3-(fluorophenyl)thioureas
(1a–j) were prepared according to the reported procedure involving the reaction of a
Scheme 1. Synthesis of some new (substituted fluorobenzoylimino)-3-aryl-4-methyl-1,3-thiazolines.

566

FLUOROBENZOYLIMINO-3-ARYLTHIAZOLINES
567
fluorbenzoyl chloride with potassium thiocyanate in acetone, followed by conden-
sation of the resulting fluorobenzoylisothiocyanate with a suitable fluoroaniline.[20]
The 1-fluoro benzoyl-3-arylthioureas are characterized by absorptions bands at
3351, 3200 cmꢁ1 for free and associated NH stretching, at 1670 for carbonyl, and
at 1240 cmꢁ1 for thiocarbonyl functionalities in their infrared (IR) spectra; singlets
at d 9.0 and 12 for HN(1) and HN(3) and peaks at 170, 179 for carbonyl and
1
thiocarbonyl are observed in their H and 13C NMR spectra, respectively.
Cyclization of thioureas (1a–j) with 2-bromoacetone in water in a basic
medium led to the formation of corresponding three series of isomeric (fluoroben-
zoylimino)-3-aryl-4-methyl-1,3-thiazolines (Scheme 1). The structures were
confirmed by slight shifting of carbonyl absorption bands toꢁ11598–1660 cmꢁ1and
=
appearance of characteristic C N stretching at 1450–1479 cm in the IR spectra
in addition to the absence of thiourea NHs absorptions. The emergence of a charac-
teristic 1H quartet at d 6.42–6.46 for H-5 and a three-proton doublet for 4-CH3 of
the thiazoline ring at d 2.07–2.10, respectively, due to the mutually coupled protons
1
with an allylic coupling constant of 0.9–1.0 Hz, was noticed in the H NMR. In 13C
NMR, the characteristic signals for olefinic carbon at d 104.4–105.1 and for methyl
carbon at 14.29–15.1 (together with signals for aromatic protons) were observed,
which agreed with the proposed structures. In the electron impact–mass spec-
trometry (EIMS), in addition to the molecular ion peak, the base peak was observed
at m=z 123, corresponding to fragment [FPhCO]þ (Table 1).
In conclusion, a green, environmentally friendly synthesis of some new (substi-
tuted fluorobenzoylimino)-3-aryl-4-methyl-1,3-thiazolines involving base-catalyzed
cyclocondensation of corresponding thioureas with 2-bromoacetone has been
achieved. The significant features include use of inexpensive, noninflammable, non-
mutagenic, noncarcinogenic solvent and the ease of isolation of products due to
phase separation.
EXPERIMENTAL
Melting points were recorded using a digital Gallenkamp (SANYO) model
1
MPD BM 3.5 apparatus and are uncorrected. H NMR spectra were determined
as CDCl3 solutions at 300 MHz using a Bruker AM-300 spectrophotometer with
tetramethylsilane (TMS) as an internal reference. 13C NMR spectra were determined
at 75MHz using a Bruker 75MHz NMR spectrometer in CDCl3 solution. IR spectra
were recorded using an Shimadzu IR 460 as KBr pellets; mass spectra (EI, 70 eV)
were recorded on a GC-MS instrument.
General Procedure for the Preparation of (Substituted
Fluorobenzoylimino)-3-aryl-4-methyl-1,3-thiazolines (2a–j)
A vigorously stirred mixture of thioureas (1a–j) (1 mmol), 2-bromoacetone
(1 mmol), and triethylamine (1 mmol) in water (20 ml) was refluxed for 40–50 min.
The progress of reaction was followed by thin-layer chromatography (TLC) using
hexane–ethyl acetate (8:2). On completion of the reaction, the products were
either filtered directly or extracted using ethyl acetate followed by drying and
concentration. Recrystallization using ethanol or methanol afforded the

568
A. SAEED AND U. SHAHEEN
(fluorobenzoylimino)-3-aryl-4-methyl-1,3-thiazolines (2a–j) as crystalline solids.
1
Table 1 gives the physicochemical and characteristic spectral data (IR, H NMR,
13C NMR, EIMS) of the products.
ACKNOWLEDGMENT
The authors gratefully acknowledge the research grant from Quaid-I-Azam
University, Islamabad.
REFERENCES
1. Klijin, J. E.; Engberts, J. B. F. N. Fast reactions ‘‘on water’’. Nature 2005, 435, 746.
2. Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B. ‘‘On
Water’’: Unique reactivity of organic compounds in aqueous suspension. Angew. Chem.
Int. Ed. 2005, 44, 3275.
3. Breslow, R.; Rizzo, C. J. Chaotropic salt effects in a hydrophobically accelerated Diels–
Alder reaction. J. Am. Chem. Soc. 1991, 113, 4340–4341.
4. Jacobson, G. B.; Lee Jr., T. C.; da Rocha, S. R. P.; Johnston, K. P. Organic synthesis in
water=carbon dioxide emulsions. J. Org. Chem. 1999, 64 (4), 1207.
5. Vicini, P.; Geronikaki, A.; Anastasia, K.; Incerti, M.; Zani, F. Synthesis and antimicrobial
activity of novel 2-thiazolylimino-5-arylidene-4-thiazolidinones. Bioorg. Med. Chem. 2006,
14, 3859.
6. (a) Zhang, A.; Kaiser, H.; Maienfisch, P.; Casida, J. E. Insect nicotinic acetylcholine
receptor: Conserved neonicotinoid specificity of [3H]imidacloprid binding site. J. Neuro-
chem. 2000, 75, 1294; (b) Maienfisch, P.; Haettenschwiler, J.; Rindlisbacher, A.; Decock,
A.; Wellmann, H.; Kayser, H. Azido-neonicotinoids as candidate photoaffinity probes for
insect nicotinic acetylcholine receptors. Chimia 2003, 57, 710.
7. (a) Hosseinimehr, S. J.; Shafiee, A.; Mozdarani, H.; Akhlagpour, S. Radioprotective
effects of 2-iminothiazolidine derivatives against lethal doses of gamma radiation in mice.
J. Radiat. Res. 2001, 42, 401; (b) Hosseinimehr, S. J.; Shafiee, A.; Mozdarani, H.;
Akhlagpour, S.; Froughizadeh, M. Radioprotective effects of 2-imino-3-[(chromone-2-yl)
carbonyl]thiazolidines against c-irradiation in mice. J. Radiat. Res. 2002, 43, 293.
8. Bae, S.; Hahn, H.-G.; Nam, K. D. Solid-phase synthesis of fungitoxic 2-imino-1,3-
thiazolines. J. Comb. Chem. 2005, 7, 7.
9. Kim, D.-S.; Jeong, Y.-M.; Park, I.-K.; Hahn, H.-G.; Lee, H.-K.; Kwon, S.-B.; Yang, S. J.;
Sohn, U. D.; Park, K.-C. A new 2-imino-1,3-thiazoline derivative, KHG22394, inhibits
melanin synthesis in mouse B16 melanoma cells. Biol. Pharm. Bull. 2007, 30, 180.
10. Pietrancosta, N.; Moumen, A.; Dono, R.; Lingor, P.; Planchamp, V.; Lamballe, F.; Ba¨hr,
M.; Kraus, J.-L.; Maina, F. Imino-tetrahydro-benzothiazole deriatives as p53 inhibitors:
Discovery of a highly potent in vivo inhibitor and its action mechanism. J. Med. Chem.
2006, 49, 3645.
11. Sondhi, S. M.; Singh, S.; Kumar, A.; Jamal, H.; Gupta, P. P. Synthesis of amidine and
amide derivatives and their evaluation for anti-inflammatory and analgesic activities.
Eur. J. Med. Chem. 2008, 30, 1.
12. Manaka, A.; Sato, M.; Aoki, M.; Tanaka, M.; Ikeda, T.; Toda, Y.; Yamanane, Y.;
Nakaike, S. 2-Acylimino-3H-thiazoline derivatives: A novel template for platelet
GPIIb=IIIa receptor antagonists. Bioorg. Med. Chem. Lett. 2001, 11, 1031.
13. Sondhi, S. M.; Singh, N.; Lahoti, A. M.; Bajaj, K.; Kumar, A.; Lozach, O.; Meijer, L.
Synthesis of acridinyl-thiazoline derivatives and their evaluation for anti-inflammatory,
analgesic, and kinase inhibition activities. Bioorg. Med. Chem. 2005, 13, 4291.

FLUOROBENZOYLIMINO-3-ARYLTHIAZOLINES
569
14. Shih, M.-H.; Ke, F.-Y. Synthesis and evaluation of antioxidant activity of sydnonyl
substituted thiazolidinone and thiazoline derivatives. J. Bioorg. Med. Chem. 2004, 12,
4633.
15. Sanemitsu, Y.; Kawamura, S.; Satoh, J.; Katayama, T.; Hashimoto, S. Synthesis and
herbicidal activity of 2-acylimino-3-phenyl-1,3-thiazolines—A new family of bleaching
herbicides. J. Pestic. Sci. 2006, 31, 305.
16. Zeng, R.-S.; Zou, J.-P.; Zhi, S.-J.; Chen, J.; Shen, Q. Novel synthesis of 1-aroyl-3-aryl-
4-substituted imidazole-2-thiones. Org. Lett. 2003, 5, 1657.
17. Singh, C. B.; Murru, S.; Kavala, V.; Patel, B. K. It is ‘‘thiazolidene-2-imine’’ and not
imidazole-2-thione as the reaction product of 1-benzoyl-3-phenylthiourea with Br2=
enolizable ketone. Org. Lett. 2006, 8, 5397.
18. Germanas, J. P.; Wang, S.; Miner, A.; Hao, W.; Ready, J. M. Discovery of small-molecule
inhibitors of tyrosinase. Bioorg. Med. Chem. Lett. 2007, 17, 6871.
19. Saeed, A.; Zaman, S.; Bolte, M. Synthesis and crystal structure of some novel
2-aroylimino-3-aryl-4-phenyl-1,3-thiazolines. Synth. Commun. 2008, 38, 2185.
20. Saeed, A.; Parvez, M. The crystal structure of 1-(4-chlorophenyl)-3-(4-methylben-
zoyl)thiourea. Cent. Eur. J. Chem. 2005, 3, 780.