Eco-friendly synthesis and insecticidal activity of some fluorinated 2-(N-arylamino)-4-arylthiazoles

Article abstract of DOI:10.1080/10426500903036014

A series of fluorinated 2-(N-arylamino)-4-arylthiazoles (3) was synthesized by the condensation of appropriate arylthioureas (2) with corresponding α-bromoacetophenones (1) by using green chemistry techniques, viz. mechanochemical mixing and microwave or

Full text of DOI:10.1080/10426500903036014

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Eco-Friendly Synthesis and Insecticidal
Activity of Some Fluorinated 2-(N-
Arylamino)-4-Arylthiazoles
Ragini Gupta a , Deepti Sharma b & Swaroop Singh c
a Department of Chemistry , Malaviya National Institute of
Technology , Jaipur, India
b Centre of Advanced Studies , Department of Chemistry, University
of Rajasthan , Jaipur, India
c Durgapura Agricultural Research Centre , Jaipur, India
Published online: 03 Jul 2010.
To cite this article: Ragini Gupta , Deepti Sharma & Swaroop Singh (2010) Eco-Friendly Synthesis and
Insecticidal Activity of Some Fluorinated 2-(N-Arylamino)-4-Arylthiazoles, Phosphorus, Sulfur, and
Silicon and the Related Elements, 185:7, 1321-1331, DOI: 10.1080/10426500903036014
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Phosphorus, Sulfur, and Silicon, 185:1321–1331, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903036014
ECO-FRIENDLY SYNTHESIS AND INSECTICIDAL
ACTIVITY OF SOME FLUORINATED
2-(N-ARYLAMINO)-4-ARYLTHIAZOLES
Ragini Gupta,1 Deepti Sharma,2 and Swaroop Singh3
1Department of Chemistry, Malaviya National Institute of Technology, Jaipur, India
2Centre of Advanced Studies, Department of Chemistry, University of Rajasthan,
Jaipur, India
3Durgapura Agricultural Research Centre, Jaipur, India
A series of fluorinated 2-(N-arylamino)-4-arylthiazoles (3) was synthesized by the conden-
sation of appropriate arylthioureas (2) with corresponding α-bromoacetophenones (1) by
using “green chemistry” techniques, viz. mechanochemical mixing and microwave or ultra-
sonic irradiation. Compared with conventional procedures, the reaction can be carried out
under milder conditions, requiring a shorter reaction time and giving higher yields following
the green chemistry methodology. All the synthesized compounds were characterized on the
basis of elemental analyses and spectral data (IR, 1H NMR, and mass spectrometry). Repre-
sentative compounds were also evaluated for their insecticidal activity against Helicoverpa
armigera, and some of them showed promising activity.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords Arylthiazoles; arylthioureas; α-bromoacetophenones; eco-friendly synthesis; in-
secticidal activity; microwave irradiation; sonochemistry
INTRODUCTION
Thiazoles and 2-aminothiazoles are important heterocyclic compounds associated
with various pharmacological and biological properties including antimicrobial,1 anti-
inflammatory,2 antitumor,3 analgesic,4 antioxidant,5 anticonvulsant,6 antihypertensive,7 hy-
poglycemic,8 and herbicidal9 activities. Further, incorporation of fluorine into organic com-
pounds enhances their biological activity; in particular the trifluoromethyl substituent has
Received 9 January 2009; accepted 8 May 2009.
The authors wish to express their thanks to Dr. K. P. Madhusudanan, Deputy Director and Head, SAIF
(Sophisticated Analytical Instrument Facility), Central Drug Research Institute (CDRI), Lucknow, India, for
elemental analyses and spectral data. The authors are also thankful to Prof. P. S.Verma, Head, Department of
Chemistry, University of Rajasthan, Jaipur, India, for providing necessary facilities and encouragement during the
present investigation. One of the authors (D.S.) is grateful to the Centre of Advanced Studies (CAS), Department
of Chemistry, University of Rajasthan, Jaipur, India, for award of JRF.
Address correspondence to Ragini Gupta, Department of Chemistry, Malaviya National Institute of Tech-
nology, Jaipur- 302017, India. E-mail: raginigupta@mnit.ac.in
1321

1322
R. GUPTA ET AL.
shown phytotoxic activity.10 Ethaboxam,11 thifluzamide,12 and metasulfovax13 are well
known commercially available fungicides containing a fluorinated thiazole moiety, widely
used in agriculture. Huang and Yang14 have also reported the microwave-assisted synthesis
of polyfluorinated 2-benzylthiobenzothiazoles that showed enhanced fungicidal activity
against R. solani, B. cinereapers, and D. gregaria. Pathak and Singh15 have also reported
some fluorinated thiazoles as potent pesticidal agents against Mesocyclops leuckratti and
observed that substitution of fluorine atom at para-position of the aryl moiety enhances the
insecticidal activity as compared to substitution by chlorine.
In view of the importance of 2-aminothiazole and its derivatives, various syn-
thetic methods have been developed from time to time, but the Hantzsch reaction of
α-halocarbonyl compounds with thioureas is the method of choice.16 Other methods in-
clude the reaction of α-haloketones with KSCN and RNH2,17 and ketones with a mixture
of NBS, thiourea, and benzoyl peroxide.18 Solid-supported syntheses have been used to
generate small organic libraries,19 and solution phase chemistry methods utilizing DMF20
as well as 1,4-dioxane21 have been reported for combinatorial libraries. Recently, many
improved methods have been reported for the synthesis of thiazoles using catalysts such
as ammonium 12-molybdophosphate (AMP) in methanol,22 β-cyclodextrin in water,23 io-
dine,24 and silica chloride,25 using a solvent such as 1-methyl-2-pyrrolidinone,26 with the
use of microwaves,27 and using ionic liquids28 and water.29 However, in spite of their po-
tential utility, many of these reported methods suffer from drawbacks such as polar and
volatile solvents, unsatisfactory yields, cumbersome product isolation procedures, and of-
ten expensive catalysts that require a longer reaction time under drastic conditions resulting
in generation of aqueous or organic solvent waste.
So the development of a milder, simpler, greener, and more efficient procedure for
the synthesis of 2-aminothiazoles is highly desirable. It is currently of prime interest to
connect research in chemistry with concerns of environmental protection. So, a number of
procedures are now recommended for green chemistry,30 involving either new eco-friendly
reagents and catalysts; selective media such as water, ionic liquids, or solvent-free reac-
tions; or a non-classical mode of activation such as ultrasound or microwaves. Inspired by
these observations and in continuation of our research in developing benign and expedi-
tious methods for organic transformations,31,32 we report in this article the environmentally
desirable synthesis of some new 2-(N-arylamino)-4-arylthiazoles (3) using solvent-free
synthetic methods (microwave irradiation and grinding) and ultrasonication, wherein not
only the reaction time has been brought down from hours to minutes in comparison to
a conventional heating process, but also results in improved yields. Representative com-
pounds were screened for their insecticidal activity against Helicoverpa armigera, showing
promising results.
Grindstone chemistry—a greatly evolved version of Toda’s method of grinding solids
together for solvent free chemical reactions, and also called ball-milling chemistry or
mechano-chemistry—is of interest in synthesizing heterocycles because it takes place
under mild conditions, in the absence of a solvent, and under eco-friendly conditions.33 In
the grindstone technique, reactions occur through generation of local heat by the grinding
of crystals of substrate and reagents by a mortar and pestle, with the transfer of a very
small amount of energy. Another solvent-free popular technique is microwave chemistry
and can be termed as E-chemistry. Microwave (MW) heating has been used for the rapid
synthesis of a variety of compounds, wherein chemical reactions are accelerated because
of selective absorption of MW energy by polar molecules, nonpolar molecules being inert

FLUORINATED 2-(N-ARYLAMINO)-4-ARYLTHIAZOLES
1323
to the MW dielectric loss.34 The MW irradiation under solvent-free conditions provides
unique chemical processes with special attributes such as enhanced reaction rates, higher
yields, greater selectivity, and ease of manipulation.35
Ultrasound has been used more and more frequently in organic synthesis.36 Activa-
tion of organic reactions with ultrasound constitutes an important and far-reaching domain
of modern sonochemistry. This is largely due to the fact that sonochemistry and the re-
cent upsurge of interest in sustainable chemistry share similar aims, such as the use of
less hazardous chemicals and environmentally benign solvents while minimizing energy
consumption and increasing the selectivity of the product.37
To the best of our knowledge, there are no reports in the literature of the preparation
of 2-(N-arylamino)-4-arylthiazoles by ultrasonication.
RESULTS AND DISCUSSION
Synthesis
2-(N-Arylamino)-4-arylthiazoles (3) were prepared by reacting α-bromoacetophen-
ones (phenacyl bromides) (1) and N-aryl substituted thioureas (2) by following the classical
Hantzsch synthesis using various techniques (Scheme 1). In the traditional approach, the
reaction proceeds with low yield (45–58%) after refluxing for 6–8 h in ethanol. In an attempt
to improve the yield of reaction and acknowledging the benefits of “green chemistry,” the
same reaction was performed under solvent-free conditions (microwave irradiation and
grinding) and ultrasound irradiation. In the grindstone technique, α-bromoacetophenones
and arylthioureas were mixed together by grinding, which was continued for a further
10–15 min to afford the desired compounds in 86–95% yield. The same reactants were
thoroughly mixed without solvent and irradiated for 2–5 min in a domestic microwave
oven to afford the title compounds in 82–94% yield. Under solvent-free conditions, the
reaction is completed within few minutes and with higher yield, due to the reason that a
eutectic mixture having uniform distribution of the reactants brings the reacting species in
closer proximity to react than in solvent. In the ultrasonic approach, α-bromoacetophenone
upon sonication with arylthiourea in an ultrasonic cleaning bath gave 90–97% yield of
corresponding thiazole in 1–2.5 h, and the comparative data of various procedures are
presented in Table I. The synthetic steps are illustrated in Scheme 1.
In the IR spectra of α-bromoacetophenones (1a–g), characteristic >C O absorp-
tion bands appear from 1720–1710 cm−1. The strong absorption band in the range
530–515 cm−1 has been attributed to C-Br vibrating modes. In the arylthioureas (2a–f),
absorption bands at 3421–3380, 3291–3150, and 1580–1540 cm−1 are attributed to NH2,
NH, and >C S stretching vibrations, respectively. The IR spectra of 2-(N-arylamino)-4-
arylthiazoles (3a–p) exhibit a broad absorption peak in the region of 3450–3100 cm−1 due
to >NH stretching vibration. The C N stretching frequencies have been assigned to the
1560–1530 cm−1 region. The bands are mixed with the phenyl ring skeletal vibrations. The
prominent peak between 1352–1330 cm−1 has been attributed to C S stretching vibration.
In the 1H NMR spectra of compounds 1a–g, CH2 protons are observed as a singlet
at δ 4.40–4.55 ppm. This downfield shift of CH2 protons is attributed to the e− withdrawing
effect of Br and C O group. Aromatic protons appear as a multiplet in the region δ
6.97–8.32 ppm. In the compounds 2a–j, a singlet at δ 10.80–10.91 ppm appears due to a
NH proton. A broad singlet at δ 3.55 ppm is attributed to the NH2 proton absorption

1324
R. GUPTA ET AL.
Y
O
S
X
C
+
C
HN
(i) / (ii) / (iii) / (iv)
CH2Br
H2N
2
1
OH
Y
HS
HN
X
C
+
C
HN
CHBr
H2O
H2S
Y
Y
X
X
N
N
NH4OH
HBr
N
H
S
NH
S
3
(i) By ultrasound method
(ii) By microwave method
(iii) By grinding method
(iv) By conventional method
3a: X=H, Y=H
3e: X=4-Cl, Y=4-Br
3f: X=4-F, Y=4-Br
3g: X=4-Br, Y=4-F
3h: X=3-Cl;4-F, Y=4-Br
3i: X=3-Cl;4-F, Y=4-Cl
3m: X=4-Br, Y=2-Cl;4-F
3n: X=4-Cl, Y=2-Cl;4-F
3o: X=3-CF3, Y=4-Br
3p: X=3-CF3,Y=4-Cl
3b: X=H, Y=4-Br
3c: X=H, Y=4-Cl
3j: X=4-Br, Y=3-CH3;4-F
3k: X=4-Cl, Y=3-Cl;4-F
3l: X=4-Br,Y=3-Cl;4-F
3d: X=4-Br, Y=4-Br
Scheme 1 (i) Ultrasound method; (ii) microwave method; (iii) grinding method; (iv) conventional method.
peak. Aromatic proton signals appear as a multiplet from δ 6.68–7.94 ppm. In the 1H NMR
spectra of 2-(N-arylamino)-4-arylthiazoles (3a–p), the methine proton at C-5 position of
thiazole moiety shows a resonance signal at δ 5.95–6.94 ppm, and a N H resonance signal
is observed in the region δ 7.31–7.91 ppm as a singlet, which is D2O exchangeble. Aromatic
protons are observed as a multiplet from δ 6.90–7.80 ppm.
Final confirmation is achieved from fast atomic bombardment (FAB) mass spectra,
which exhibit a molecular ion peak (M+) of compounds 3a–p corresponding to their
molecular masses. Mass spectrum of compound 3h showed a characteristic molecular ion
cluster m/z at 382/384 ([M]+, 52.63%) due to the presence of isotopic bromine and a
chlorine atom, along with a base peak at 136 ([M+-C9H5BrClF], 100%), and other peaks
at 308 (18.42), 290 (13.15), 273 (13.15), 168 (10.52), 155 (65.78), 120 (50), 107 (36.84),
88 (23.68), 76 (21.05) were observed.
The presence of fluorine was confirmed by 19F NMR spectra, where the C F signal
was observed at δ −114.84 to −116.78 ppm (compounds 3f–n) and the CF3 signal38 at δ
−62.98 to −63.28 ppm in the case of compounds 3o and 3p.

FLUORINATED 2-(N-ARYLAMINO)-4-ARYLTHIAZOLES
1325
Table I Yield (%) and time (min) of the synthesis of 2-(N-arylamino)-4-arylthiazoles (3a–p)
Yield (%)
(c)
Time (min)
(b) (c)
Compd. no.
(a)
(b)
(d)
(a)
(d)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
90.0
91.0
88.2
91.5
94.8
91.0
92.4
97.0
97.3
89.0
90.0
96.0
96.0
95.5
97.0
97.0
82.0
87.7
85
86.2
89.0
87.1
91.0
93.0
90.5
91.8
94.0
95.5
84.6
88.3
93.4
94.0
94.0
95.6
95.0
45.0
47.1
46.3
52.5
54.7
53.8
56.0
58.2
57.0
52.0
51.0
58.6
57.5
56.3
58.2
58.0
120
90
90
3
3,5
3.5
3
3
3.5
4
3.5
3.5
5
4.5
4
15
10
12
10
12
15
15
15
15
20
15
12
10
14
12
10
480
450
435
420
420
450
435
480
480
510
450
435
435
450
360
360
90.0
92.4
90.0
90.0
92.1
92.2
82.7
82.6
92.3
92.0
92.8
93.8
94.0
90.0
120
135
135
150
150
150
120
75
75
120
60
4
4
2.5
2
60
(a) Ultrasound method; (b) microwave method; (c) grinding method; (d) conventional method.
Insecticidal Activity
In the present study. four thiazoles, 3h, 3j, 3o, and 3p, were screened for their
insecticidal activity, which was measured on third instar larvae of Helicoverpa armigera at
the Department of Entomology, Agricultural Research Station, Durgapura, Jaipur, India, by
food dipping method.39 Statistical analysis was carried out using completely randomized
design (CRD) technique.40 Please see the Supplemental Materials (available online) for
complete details.
EXPERIMENTAL
All the melting points were determined in open glass capillary tubes and are uncor-
rected. The IR spectra (vmax in cm−1) were recorded on FT IR model Shimadzu-8400S
grating infrared spectrophotometer in KBr pellets. 1H NMR and 19F spectra were measured
on JEOL-AL 300 spectrophotometer at 300 MHz, respectively, using TMS as an internal
standard (chemical shift in δ ppm) for PMR and CF3COOH (TFA) as an external standard
1
for 19F NMR and CDCl3 as a solvent. The IR, H NMR, and 19F spectra were recorded
at the Department of Chemistry, University of Rajasthan, Jaipur, India. The FAB mass
spectra were recorded on JEOL SX 102/DA-6000 mass spectrometer/data system using
argon/xenon (6 KV, 10 mA) as the FAB gas. Elentar Vario EL III automatic CHNS analyzer
was used for elemental analyses. The FAB mass spectra and CHNS analyses were recorded
at Central Drug Research Institute (CDRI), Lucknow, India. Microwave irradiation was
carried out in an LG MS-194A household microwave oven with maximum 800 power and
2450 MHz frequency. Sonication was performed in a Toshcon model SW 4 cleaner (with
a frequency of 37 KHz and operating at maximum power of 150 W). The purity of the
compounds was checked by TLC using silica gel (60–120 mesh) as adsorbent, UV light,
or iodine accomplished visualization. All common reagents and solvents were used as

1326
R. GUPTA ET AL.
obtained from commercial suppliers without further purification. α–Bromoacetophenones
(phenacyl bromides) (1) and N-arylthioureas (2) were prepared by the methods in the
literature.41–42
General Procedures for the Preparation of 2-(N-Arylamino)-4-
arylthiazoles (3a–p)
Method (i). A mixture of arylthiourea (2) (1 mmol) and phenacyl bromide (1)
(1 mmol) were ground together in a mortar. Then this mixture was transferred into a pyrex
conical flask (250 mL). Ethanol (10 mL) was added to it, and then it was sonicated in an
ultrasonic cleaning bath for the time period as indicated at room temperature. The reaction
flask was immersed in the region of highest intensity from the base of the ultrasonic
bath. The bath temperature (30–35◦C) was controlled by addition or removal of water.
Sonication was continued until the starting reactants disappeared as indicated by TLC.
After the completion of the reaction, the mixture was treated with ammonia to liberate
the free base, which was then filtered, washed with water, dried, and recrystallized from
ethanol to afford the desired product.
Method (ii). Phenacyl bromide (1) (1 mmol) and the appropriate arylthiourea (2)
(1 mmol) were mixed thoroughly using a pestle and mortar. The reaction mixture was then
transferred into a conical flask (100 mL) and exposed to microwave irradiation for 2–5 min
(intermittently with 1 min cooling interval) at maximum power (800 W). Final temperature
of the reaction mixture was measured by immersing a thermometer at the end of the reaction
(65–70◦C). The progress of the reaction was monitored by TLC using C6H6:Pet ether, 80:20
as the solvent system. After cooling to room temperature, the thiazole salt so obtained was
neutralized by the addition of a dilute solution of ammonia. The crude product was extracted
into methylene chloride (2 × 10 mL) and dried over anhydrous sodium sulfate. The solvent
was removed under reduced pressure, and the residue was recrystallized from ethanol to
afford pure 1,3-thiazoles.
Method (iii). A mixture of α-bromoacetophenone (1) (1 mmol) and substituted
arylthiourea (2) (1 mmol) was thoroughly mixed in a mortar followed by grinding until the
completion of the reaction as indicated by TLC (10–15 min). Ammonia solution was added
to generate the free base of the compound, which was then washed then air dried to afford
the crude product. The pure thiazole was obtained by recrystallization from ethanol.
Method (iv). A mixture of the appropriate arylthiourea (2) (1 mmol) and phenacyl
bromide (1) (1 mmol) in ethanol (25 mL) was refluxed for 6–8 h, with occasional shaking
on a water bath. After cooling, the precipitated solid was separated and then suspended in
water/methanol mixture. Free base was obtained by treating the corresponding hydrobro-
mide salt with ammonia solution until it was alkaline. The precipitated mass was filtered
off, washed several times with water, and recrystallized from ethanol.
Preparation of 2-Phenylamino-4-phenylthiazole (3a)
Yield: Method (i) 90%, method (ii) 82%, method (iii) 86.2%, method (iv) 45%;
Time (min): (i) 120, (ii) 3, (iii) 15, (iv) 480; mp 136◦C; IR (KBr)v: 3100 (NH str.), 3018
(aromatic C H str.), 1531 (C N str.), 1330 (C S str), 1600 (aromatic C C str.) cm−1
;
1H NMR (CDCl3) δ: 7.31 (s, NH, 1H), 6.90–7.23 (m, ArH, 10H), 5.95 (s, Thiazole H, 1H);
FABMS (%) m/z: 252 [M+] (100), 176 (36.01), 160 (15.12), 85 (32.14); Anal. Calcd. (%)
for C15H12N2S: C, 71.42; H, 4.76; N, 11.10; S, 12.60. Found: C, 71.27; H, 4.62; N, 11.15;
S, 12.52.

FLUORINATED 2-(N-ARYLAMINO)-4-ARYLTHIAZOLES
1327
Preparation of 2-Phenylamino-4-(4-bromophenyl)thiazole (3b)
Yield: Method (i) 91%, method (ii) 87.7%, method (iii) 89%, method (iv) 47.1%;
Time (min): (i) 90, (ii) 3.5, (iii) 10, (iv) 450; mp 195◦C; IR (KBr)v: 3120 (NH str.), 3020
(aromatic C H str.), 1535 (C N str.), 1330 (C S str.), 1580 (aromatic C C str.), 560
1
(C-Br str.) cm−1; H NMR (CDCl3) δ: 7.42 (s, NH, 1H), 6.95–7.38 (m, ArH, 9H), 5.95
(s, Thiazole H, 1H); FABMS (%) m/z: 330[M+] (100)/332[M+2] (isotopic cluster), 251
(28.12), 175 (15.24), 148 (36.21), 72 (62.09); Anal. Calcd. (%) for C15H11BrN2S: C, 54.54;
H, 3.33; N, 8.48; S, 9.69. Found: C, 54.50; H, 3.38; N, 8.42; S, 9.63.
Preparation of 2-Phenylamino-4-(4-chlorophenyl)thiazole (3c)
Yield: Method (i) 88.2%, method (ii) 85%, method (iii) 87.1%, method (iv) 46.3%;
Time (min): (i) 90, (ii) 3.5, (iii) 12, (iv) 435; mp 190◦C; IR (KBr)v: 3150 (NH str.), 3020
(aromatic C H str.), 1535 (C N str.), 1330 (C S str.), 1590 (aromatic C C str.), 615
1
(C-Cl str.) cm−1; H NMR (CDCl3) δ: 7.43 (s, NH, 1H), 6.91–7.20 (m, ArH, 9H), 5.84
(s, Thiazole H, 1H); FABMS (%) m/z: 286[M+] (78.65)/288[M+2] (isotopic cluster), 251
(35.14), 175 (42.63); Anal. Calcd. (%) for C15H11ClN2S: C, 62.93; H, 3.84; N, 9.79; S,
11.18. Found: C, 62.85; H, 3.81; N, 9.71; S, 11.21.
Preparation of 2-(4-Bromophenylamino)-4-(4-bromophenyl)thiazole
(3d)
Yield: Method (i) 91.5%, method (ii) 90%, method (iii) 91%, method (iv) 52.5%;
Time (min): (i) 90, (ii) 3, (iii) 10, (iv) 420; mp 150◦C; IR (KBr)v: 3275 (NH str.), 3030
(aromatic C H str.), 1538 (C N str.), 1335 (C S str.), 1595 (aromatic C C str.), 565 (C-
Br) cm−1; 1H NMR (CDCl3) δ: 7.65 (s, NH, 1H), 6.94–7.28 (m, ArH, 8H), 6.85 (s, Thiazole
H, 1H); FABMS (%) m/z: 408[M+] (100)/410[M+2] (isotopic cluster), 329 (56.23), 250
(34.12), 174 (22.87); Anal. Calcd. (%) for C15H10Br2N2S: C, 44.11; H, 2.45; N, 6.86; S,
7.84. Found: C, 44.24; H, 2.32; N, 6.82; S, 7.87.
Preparation of 2-(4-Chlorophenylamino)-4-(4-bromophenyl)thiazole (3e)
Yield: Method (i) 94.8%, method (ii) 92.4%, method (iii) 93%, method (iv) 54.7%;
Time (min): (i) 120, (ii) 3, (iii) 12, (iv) 420; mp 155◦C; IR (KBr)v: 3315 (NH str.), 3040
(aromatic C H str.), 1535 (C N str.), 1335 (C S str.), 1594 (aromatic C C str.), 560
1
(C-Br), 620 (C-Cl) cm−1; H NMR (CDCl3) δ: 7.65 (s, NH, 1H), 7.27–7.56 (m, ArH,
8H), 6.83 (s, Thiazole H, 1H); FABMS (%) m/z: 364[M+] (51.43)/366[M+2]/368[M+4]
(isotopic cluster), 285 (100), 250 (43.26), 174 (25.68), 133 (18.17); Anal. Calcd. (%) for
C15H10BrClN2S: C, 49.45; H, 2.74; N, 7.69; S, 8.79. Found: C, 49.42; H, 2.69; N, 7.64; S,
8.71.
Preparation of 2-(4-Fluorophenylamino)-4-(4-bromophenyl)thiazole (3f)
Yield: Method (i) 91%, method (ii) 90%, method (iii) 90.5%, method (iv) 53.8%;
Time (min): (i) 135, (ii) 3.5, (iii) 15, (iv) 450, mp 137◦C; IR (KBr)v: 3320 (NH str.), 3040
(aromatic C H str.), 1540 (C N str.), 1340 (C S str.), 1595 (aromatic C C str.), 562
(C-Br), 1141 (C-F) cm−1; 1H NMR (CDCl3) δ: 7.85 (s, NH, 1H), 7.24–7.73 (m, ArH, 8H),

1328
R. GUPTA ET AL.
6.84 (s, Thiazole H, 1H); 19F NMR (CDCl3) δ: −116.62 (s, F); FABMS (%) m/z: 348[M+]
(100)/350[M+2] (isotopic cluster), 269 (71.28), 250 (34.78), 202 (15.17); Anal. Calcd. (%)
for C15H10BrFN2S: C, 51.72; H, 2.87; N, 8.04; S, 9.19. Found: C, 51.68; H, 2.72; N, 8.07;
S, 9.09.
Preparation of 2-(4-Bromophenylamino)-4-(4-fluorophenyl)thiazole (3g)
Yield: Method (i) 92.4%, method (ii) 90%, method (iii) 91.8%, method (iv) 56%;
Time (min): (i) 135, (ii) 4, (iii) 15, (iv) 435, mp 131◦C; IR (KBr)v: 3320 (NH str.), 3040
(aromatic C H str.), 1540 (C N str.), 1340 (C S str.), 1595 (aromatic C C str.), 570
(C-Br), 1130 (C-F) cm−1; 1H NMR (CDCl3) δ: 7.62 (s, NH, 1H), 7.10–7.54 (m, ArH, 8H),
6.75 (s, Thiazole H, 1H); 19F NMR (CDCl3) δ: −115.92 (s, F); FABMS (%) m/z: 348[M+]
(65.34)/350[M+2] (isotopic cluster), 329 (54.27), 299 (100), 144 (17.14); Anal. Calcd. (%)
for C15H10BrFN2S: C, 51.72; H, 2.87; N, 8.04; S, 9.19. Found: C, 51.69; H, 2.93; N, 8.09;
S, 9.10.
Preparation of 2-(3-Chloro-4-fluorophenylamino)-4-(4-bromophenyl)
thiazole (3h)
Yield: Method (i) 97%, method (ii) 92.1%, method (iii) 94%, method (iv) 58.2%;
Time (min): (i) 150, (ii) 3.5, (iii) 15, (iv) 480, mp 180◦C; IR (KBr)v: 3370 (NH str.), 3050
(aromatic C H str.), 1542 (C N str.), 1345 (C S str.), 1600 (aromatic C C str.), 560
(C-Br), 625 (C-Cl), 1150 (C-F) cm−1; 1H NMR (CDCl3) δ: 7.82 (s, NH, 1H), 7.01–7.60 (m,
ArH, 7H), 6.84 (s, Thiazole H, 1H);19F NMR (CDCl3) δ: −114.99 (s, F); FABMS (%) m/z:
382[M+] (52.63)/384[M+2]/386[M+4] (isotopic cluster), 308 (18.42), 290 (13.15), 273
(13.15), 168(10.52), 155(65.78), 136(100)120(50);Anal. Calcd. (%)forC15H9BrClFN2S:
C, 47.12; H, 2.35; N, 7.32; S, 8.37. Found: C, 47.08; H, 2.29; N, 7.26; S, 8.34.
Preparation of 2-(3-Chloro-4-fluorophenylamino)-4-(4-chlorophenyl)
thiazole (3i)
Yield: method (i) 97.3%, method (ii) 92.2%, method (iii) 95.5%, method (iv) 57%;
Time (min): (i) 150, (ii) 3.5, (iii) 15, (iv) 480; mp 110◦C; IR (KBr)v: 3380 (NH str.), 3050
(aromatic C H str.), 1545 (C N str.), 1345 (C S str.), 1610 (aromatic C C str.), 650
(C-Br), 1150 (C-F) cm−1; 1H NMR (CDCl3) δ: 7.83 (s, NH, 1H), 7.05–7.61 (m, ArH, 7H),
6.86 (s, Thiazole H, 1H);19F NMR (CDCl3) δ: −114.84 (s, F); FABMS (%) m/z: 338[M+]
(56.23)/340[M+2] (isotopic cluster), 303 (47.38), 268 (31.25), 249 (18.23), 155 (100);
Anal. Calcd. (%) for C15H9Cl2FN2S: C, 53.25; H, 2.66;N,8.28, S,9.46. Found: C, 53.16;
H, 2.60; N, 8.21; S, 9.43.
Preparation of 2-(4-Bromophenylamino)-4-(4-fluoro-3-methylphenyl)
thiazole (3j)
Yield: Method (i) 89%, method (ii) 82.7%, method (iii) 84.6%, method (iv) 52%;
Time (min): (i) 150, (ii) 5, (iii) 20, (iv) 510; mp 170◦C; IR (KBr)v: 3310 (NH str.), 3030
(aromatic C H str.), 2990 (aliphatic C-H str.), 1535 (C N str.), 1340 (C S str.), 1590
(aromatic C C str.), 560 (C-Br) cm−1; 1H NMR (CDCl3) δ: 7.56 (s, NH, 1H), 7.10–7.47

FLUORINATED 2-(N-ARYLAMINO)-4-ARYLTHIAZOLES
1329
(m, ArH, 7H), 5.95 (s, Thiazole H, 1H); 1.25 (s, CH3, 3H); 19F NMR (CDCl3) δ: −115.33
(s, F); FABMS (%) m/z: 362[M+] (100)/364[M+2] (isotopic cluster), 347(42.65), 328
(18.64), 249 (15.09), 173 (64.28); Anal. Calcd. (%) for C16H12BrFN2S: C, 53.03; H, 3.31;
N, 7.73; S, 8.83. Found: C, 53.08; H, 3.25; N, 7.65; S, 8.80.
Preparation of 2-(4-Chlorophenylamino)-4-(3-chloro-4-fluorophenyl)
thiazole (3k)
Yield: Method (i) 90%, method (ii) 82.6%, method (iii) 88.3%, method (iv) 51%;
Time (min): (i) 120, (ii) 4.5, (iii) 15, (iv) 450; mp 168◦C; IR (KBr)v: 3380 (NH str.),
3052 (aromatic C H str.), 1546 (C N str.), 1348 (C S str.), 1610 (aromatic C C str.),
1
615 (C-Cl) cm−1; H NMR (CDCl3) δ: 7.74 (s, NH, 1H), 7.18–7.70 (m, ArH, 7H), 6.82
(s, Thiazole H, 1H); 19F NMR (CDCl3) δ: −115.18 (s, F); FABMS (%) m/z: 338[M+]
(46.14)/340[M+2] (isotopic cluster), 319 (52.15), 284 (37.33), 249 (41.24), 208 (100);
Anal. Calcd. (%) for C15H9Cl2FN2S: C, 53.25; H, 2.66; N, 8.28; S, 9.46. Found: C, 53.29;
H, 2.62; N, 8.21; S, 9.44.
Preparation of 2-(4-Bromophenylamino)-4-(3-chloro-4-fluorophenyl)
thiazole (3l)
Yield: Method (i) 96%, method (ii) 92.3%, method (iii) 93.4%, method (iv) 58.6%;
Time (min): (i) 75, (ii) 4, (iii) 12, (iv) 435; mp 177◦C; IR (KBr)v: 3370 (NH str.), 3050
(aromatic C H str.), 1543 (C N str.), 1346 (C S str.), 1600 (aromatic C C str.), 565
1
(C-Br) cm−1; H NMR (CDCl3) δ: 7.63 (s, NH, 1H), 7.01–7.65 (m, ArH, 7H), 6.76 (s,
Thiazole H, 1H); 19F NMR (CDCl3) δ: −114. 95 (s, F); FABMS (%) m/z: 382[M+]
(54.52)/384[M+2]/386[M+4] (isotopic cluster), 363 (41.29), 328 (78.14), 249 (64.59),
173 (15.85), 132 (100); Anal. Calcd. (%) for C15H9BrClFN2S C, 47.12; H, 2.35; N, 7.32;
S, 8.37. Found: C, 47.01; H, 2.30; N, 7.29; S, 8.33.
Preparation of 2-(4-Bromophenylamino)-4-(2-chloro-4-fluorophenyl)
thiazole (3m)
Yield: Method (i) 96%, method (ii) 92%, method (iii) 94%, method (iv) 57.5%;
Time (min): (i) 75, (ii) 4, (iii) 10, (iv) 435; mp 174◦C; IR (KBr)v: 3410 (NH str.), 3048
(aromatic C H str.), 1540 (C N str.), 1345 (C S str.), 1600 (aromatic C C str.), 560
(C-Br), 620 (C-Cl) cm−1; 1H NMR (CDCl3) δ: 7.64 (s, NH, 1H), 7.02–7.66 (m, ArH, 7H),
6.75 (s, Thiazole H, 1H);19F NMR (CDCl3) δ: −116.67 (s, F); FABMS (%) m/z: 382[M+]
(100)/384[M+2]/386[M+4] (isotopic cluster), 303 (81.28), 268 (75.79), 249 (45.03), 208
(31.93); Anal. Calcd. (%) for C15H9BrClFN2S: C, 47.12; H, 2.35; N, 7.32; S, 8.37. Found:
C, 47.05; H, 2.28; N, 7.21; S, 8.32.
Preparation of 2-(4-Chlorophenylamino)-4-(2-chloro-4-fluorophenyl)
thiazole (3n)
Yield: Method (i) 95.5%, method (ii) 92.8%, method (iii) 94%, method (iv) 56.3%;
Time (min): (i) 120, (ii) 4, (iii) 14, (iv) 450; mp 165◦C; IR (KBr)v: 3410 (NH str.), 3045
(aromatic C H str.), 1540 (C N str.), 1345 (C S str.), 1610 (aromatic C C str.), 650

1330
R. GUPTA ET AL.
(C-Cl), 1160 (C-F) cm−1; 1H NMR (CDCl3) δ: 7.82 (s, NH, 1H), 7.16–7.76 (m, ArH, 7H),
6.80 (s, Thiazole H, 1H);19F NMR (CDCl3) δ: −116.78 (s, F); FABMS (%) m/z: 338[M+]
(65.14)/340[M+2] (isotopic cluster), 319 (25.09), 284 (100), 249 (50.25); Anal. Calcd. (%)
for C15H9Cl2FN2S: C, 53.25; H, 2.66; N, 8.28; S, 9.46. Found: C, 53.18; H, 2.70; N, 8.22;
S, 9.43.
Preparation of 2-(3-Trifluoromethylphenylamino)-4-(4-bromophenyl)
thiazole (3o)
Yield: Method (i) 97%, method (ii) 93.8%, method (iii) 95.6%, method (iv) 58.2%;
Time (min): (i) 60, (ii) 2.5, (iii) 12, (iv) 360; mp 140◦C; IR (KBr)v: 3450 (NH str.), 3055
(aromatic C H str.), 1555 (C N str.), 1350 (C S str.), 1615 (aromatic C C str.), 570
(C-Cl), 1190 (C-F) cm−1; 1H NMR (CDCl3) δ: 7.91 (s, NH, 1H), 7.27–7.69 (m, ArH, 8H),
6.90 (s, Thiazole H, 1H);19F NMR (CDCl3) δ: −63.28 (s, CF3); FABMS (%) m/z: 398[M+]
(100)/400[M+2] (isotopic cluster), 329 (48.17), 250 (54.08), 234 (21.15); Anal. Calcd. (%)
for C16H10BrF3N2S: C, 48.24; H, 2.51; N, 7.03; S, 8.04. Found: C, 48.20; H, 2.57; N, 7.09;
S, 8.08.
Preparation of 2-(3-Trifluoromethylphenylamino)-4-(4-chlorophenyl)
thiazole (3p)
Yield: Method (i) 97%, method (ii) 94%, method (iii) 95%, method (iv) 58%; Time
(min): (i) 60, (ii) 2, (iii) 10, (iv) 360; mp 85◦C; IR (KBr)v: 3452 (NH str.), 3060 (aromatic
C H str.), 1560 (C N str.), 1352 (C S str.), 1620 (aromatic C C str.), 560 (C-Br), 625
(C-Cl);1195 (C-F) cm−1; 1H NMR (CDCl3) δ: 7.91 (s, NH, 1H), 7.25–7.80 (m, ArH, 8H),
6.94 (s, Thiazole H, 1H);19F NMR (CDCl3) δ: −62.98 (s, CF3); FABMS (%) m/z: 354[M+]
(100)/356[M+2] (isotopic cluster), 285 (25.85), 250 (41.57), 174 (56.04), 158 (63.21);
Anal. Calcd. (%) for C16H10ClF3N2S: C, 54.23; H, 2.82; N, 7.90; S, 9.03. Found: C, 54.18;
H, 2.74; N, 7.86; S, 9.09.
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