Bismuth chloride mediated synthesis, antimicrobial, and anti-inflammatory activities of new 4-aryl-2-amino thiazoles

Article abstract of DOI:10.1080/10426500701842019

Synthesis of 4-aryl-2-Amino thiazoles (3a-u), (4a-c), and (5a-c) was achieved from the reaction of 4-butyl phenacyl chlorides (2a-c) with N-substituted thioureas, in the presence of Bismuth Chloride. The antimicrobial and anti-inflammatory activities of the final products were also studied. Copyright Taylor & Francis Group, LLC.

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Bismuth Chloride Mediated
Synthesis, Antimicrobial, and
Anti-Inflammatory Activities of
New 4-Aryl-2-Amino Thiazoles
T. Giridhar a , R. Buchi Reddy b , A. Sunil Kumar c &
G. V. P. Chandra Mouli c
a Shodhana Laboratories Ltd. Jeedimetla,
Hyderabad, India
b Inogent Laboratories Pvt. Ltd., Hyderabad, India
c Department of Chemistry, National Institute of
Technology, Warangal, A.P, India
Version of record first published: 28 Jul 2008.
To cite this article: T. Giridhar , R. Buchi Reddy , A. Sunil Kumar & G. V. P. Chandra
Mouli (2008): Bismuth Chloride Mediated Synthesis, Antimicrobial, and Anti-
Inflammatory Activities of New 4-Aryl-2-Amino Thiazoles, Phosphorus, Sulfur, and
Silicon and the Related Elements, 183:8, 2058-2072
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Phosphorus, Sulfur, and Silicon, 183:2058–2072, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701842019
Bismuth Chloride Mediated Synthesis, Antimicrobial,
and Anti-Inflammatory Activities of New 4-Aryl-2-Amino
Thiazoles
T. Giridhar,1 R. Buchi Reddy,2 A. Sunil Kumar,3
and G. V. P. Chandra Mouli3
1Shodhana Laboratories Ltd. Jeedimetla, Hyderabad, India
2Inogent Laboratories Pvt. Ltd. Hyderabad, India
3Department of Chemistry, National Institute of Technology,
Warangal, A.P, India
Synthesis of 4-aryl-2-Amino thiazoles (3a–u), (4a–c), and (5a–c) was achieved
from the reaction of 4-butyl phenacyl chlorides (2a–c) with N-substituted thioureas,
in the presence of Bismuth Chloride. The antimicrobial and anti-inflammatory
activities of the final products were also studied.
Keywords 4-aryl-2-amino thiazoles; 4-butyl phenacyl chlorides; Bismuth chloride
INTRODUCTION
Aminothiazole derivatives exhibit anaesthetic,1 bactericidal and fungi-
cidal activites.2 It is also reported that the derivatives of fluro-aryl
thiazoles are very active, not only as antiarthritic agents, but act as
immunomodulators.3 Aryl amino thiazoles also possess cardio tonic and
antiallergic activities.4
The wide spectrum of biological activities of amino thiazoles incul-
cated enthusiasm in us, to synthesize a series of new 4-aryl-2-amino-
thiazoles and to study their anti-microbial and anti-inflammatory ac-
tivities. In the present program, the target 4-aryl-2-aminothiazole
derivatives were synthesized by the condensation of substituted
phenacyl chlorides with different thioureas. The cyclizing agents tried
were poly phosphoric acid (PPA), poly phosphoric ester (PPE), but the
yields were not satisfactory and the reaction needs prolonged heating
for completion. Therefore, there was a need to search for a better cycliz-
ing agent or catalyst with regards to toxicity, handling, easy availability,
Received 11 March 2007; accepted 24 October 2007.
Address correspondence to G. V. P. Chandramouli, Department of Chemistry, National
Institute of Technology, Warangal-04, A.P., India. E-mail: gvpc 2000@yahoo.co.in
2058

New 4-Aryl-2-amino Thiazoles
2059
SCHEME 1 a = n-butyl; b = isobutyl; and c = ter-butyl.
and operational simplicity. Bismuth (III) halides are inexpensive, rel-
atively non-toxic, and insensitive to small amounts of water and en-
vironmentally benign reagents, which have been used as mild Lewis
catalysts for an array of synthetic organic reactions.5
RESULTS AND DISCUSSION
In continuation of our work on synthesis of new heterocyclics,6 we are
gratified to report the Bismuth chloride mediate synthesis and biolog-
ical activity of new-4-aryl-2-amino thiazoles herein. It is interesting
to note that the yields increased and the reaction times were reduced
when BiCl3 in DCM was employed (Scheme I).
When Guanyl derivative of thiourea reacted with phenacyl chlorides,
compounds 4a–c were obtained. Similarly, compounds 5a–c were ob-
tained by the acetylation of the products formed when N-methyl urea
reacted with compounds 2a–c. When we attempted to synthesize the
unreported p-butyl phenacyl chlorides (2a–c), by Friedel-Crafts elec-
trophilic attack of ClCH2COCl upon butyl benzenes in the presence of
AlCl3, mixtures of O- & P- substituted products were obtained. How-
ever, the yields of Para products increased up to 90–95% by adding
catalytic amounts of BiCl3. N-substituted thioureas7(Scheme 2) were
prepared in the present scheme by an improved method, using BiCl3
catalyst.

2060
T. Giridhar et al.
TABLE I Yields and Reaction Times of 4-Aryl-2-N-substituted Amino
Thiozoles with Different Cyclizing Agents
% Yield (Reaction Time in hours)
By using By using
By using
Bicl3/DCM
Compound
R
R1
PPA
PPE
3a
3b
3c
3d
3e
3f
3g
3h
3i
n-butyl
iso-butyl
tert-butyl
n-butyl
iso-butyl
tert-butyl
n-butyl
iso-butyl
tert-butyl
n-butyl
iso-butyl
tert-butyl
n-butyl
iso-butyl
tert-butyl
n-butyl
iso-butyl CH2CH2-C6H4(OCH3)P
tert-butyl CH2CH2-C6H4(OCH3)P
n-butyl
iso-butyl
tert-butyl
n-butyl
iso-butyl
tert-butyl
n-butyl
H
H
H
CH3
CH3
CH3
Ph
Ph
Ph
30 (8)
44 (6)
37 (5)
23 (7)
35 (8)
27 (6)
21 (7)
23 (8)
28 (7)
30 (8)
29 (7)
32 (6)
28 (7)
25 (6)
42 (7)
38 (8)
18 (5)
22 (6)
27 (7)
23 (8)
32 (6)
11 (5)
17 (7)
28 (8)
22 (8)
16 (7)
26 (6)
42 (6)
51 (4)
48 (6)
36 (5)
42 (7)
48 (5)
16 (4)
31 (5)
35 (5)
36 (5)
27 (6)
35 (4)
37 (5)
32 (4)
38 (5)
42 (6)
27 (5)
29 (4)
32 (4)
44 (5)
48 (6)
19 (6)
22 (8)
19 (6)
20 (6)
21 (5)
23 (6)
68 (1.0)
90 (1.5)
97 (1.5)
58 (1.5)
78 (1.0)
81 (2.0)
52 (2.0)
58 (1.5)
60 (1.5)
68 (2.0)
57 (1.5)
65 (1.0)
70 (2.0)
60 (1.0)
54 (2.0)
77 (2.0)
54 (2.5)
62 (2.0)
51 (1.5)
55 (2.0)
64 (1.5)
42 (15)
35 (1.0)
35 (1.5)
41 (1.5)
38 (2.0)
52 (1.0)
3j
3k
3l
CH2Ph
CH2Ph
CH2Ph
3m
3n
3o
3p
3q
3r
3s
3t
3u
4a
4b
4c
5a
5b
5c
CH2CH2Ph
CH2CH2Ph
CH2CH2 Ph
CH2CH2-C6H4(OCH3)P
COCH3
COCH3
COCH3
—
—
—
—
—
iso-butyl
tert-butyl
—
The IR Spectra of Aryl amino thiazoles exhibit absorption band
around 3300–3100 cm−1 due to NH bond. The IR spectral band around
1580 10 cm−1 is due to C
N and C
C stretching vibrations. The
1H NMR chemical shifts around δ 7.3–δ 7.9 indicate the aromatic pro-
tons of 4-aryl systems. The hetero aromatic proton of the thiazole ring is
present at δ 5.5–5.7.8 The NH proton appears as a broad singlet around
δ 5.2–5.4, which disappears by D2O exchange. The proton present in the
n-butyl side chain of the aromatic ring produces characteristic signals.
The benzylic protons appear as triplet near δ 2.5–2.7. The end methyl
of n-butyl is observed as triplet at δ 0.8–1.0.

New 4-Aryl-2-amino Thiazoles
2061
SCHEME 2
Similarly, characteristic signals are observed in 1HNMR for isobutyl
side chain. The benzylic protons appear as a doublet around δ 2.5–2.6.
The methyl proton is observed as a multiplet around δ 1.8–2.0. The gem
dimethyls are seen around δ 0.9–1.0 as a doublet. The ter-butyl protons
are observed as a singlet at δ 2.2–2.5 and the N-CH3 protons appear as
a singlet at δ 3.8. The mass spectra show intense molecular ion peaks
along with prominent M + 2 peaks. The general fragmentation includes
the loss of alkyl side chains.
CONCLUSION
In conclusion, BiCl3 acts as an efficient catalyst for the synthesis of
4-aryl-2-amino thiazoles. BiCl3 catalyst is much better than PPA and
PPE, in terms of increased yields, decreased reaction timing, ease of
operation, and in non-toxic character.
ANTIMICROBIAL ACTIVITY
The elementary antibacterial9 and antifungal10 screening tests were
conducted following the standard methods (Table II). The gram-
negative bacteria used were Escherichia coli (E.C)and pseudomonas
aeruginosa (P.A), and Bacillus subtilis (B.S) and Staphylococcus au-
reus (S.A) were the gram-positive bacteria used. Ciprofloxacin (CF) was
used as reference standard for antibacterial activity. The fungus used
for testing was Candida albicans (C.A). Fluconazole (FZ) was employed
as a reference standard for anti-fungal activity.
All the substituted thiozoles exhibit lower antibacterial activity
when compared to the standard. But, many of these final compounds
exhibit strong anti-fungal activity of comparable range with that of the
reference standard namely, the Fluconazole.
ANTI-INFLAMMATORY ACTIVITY
Screening test of all the substituted thiazoles for anti-inflammatory ac-
tivity was conducted by carrageenin-induced rat-paw edema model,11

2062
T. Giridhar et al.
TABLE II Antimicrobial Activity Studies of 4-Aryl-2-N-Substituted
Amino Thiozoles
Anti-fungal
Antibacterial activity zone
activity zone
diameter (mm)
diameter (mm)
Compound
Concentration µg/ml
BS
SA
EC
PA
CA
3a
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
8.5
9.0
8.5
9.0
8.0
8.5
8.5
9.0
8.0
8.5
8.0
8.5
9.0
9.5
8.5
9.0
8.0
8.5
7.0
7.5
8.0
8.5
8.0
9.0
8.5
9.5
8.0
8.5
9.0
9.5
8.0
8.5
7.5
7.5
8.0
9.0
8.0
8.5
7.5
8.0
8.0
8.5
8.0
8.5
8.5
9.0
8.0
8.5
8.0
9.0
9.0
9.5
9.0
9.5
8.0
8.5
8.0
9.0
9.0
9.5
7.5
8.0
7.5
8.5
8.0
8.5
8.0
8.5
8.5
9.5
9.5
9.5
8.5
8.5
8.0
8.5
7.5
8.5
8.0
9.0
8.5
9.5
9.0
9.5
11.5
12.0
13.0
13.5
12.0
12.5
11.5
12.5
11.5
12.0
11.0
12.5
12.0
13.0
11.0
12.0
11.0
11.5
10.5
11.0
11.0
11.5
11.5
12.0
11.0
11.5
11.0
12.0
11.5
12.0
11.5
12.5
10.5
11.0
9.0
12.0
13.0
12.5
13.5
13.0
13.5
12.0
13.0
12.0
13.0
12.0
12.5
12.0
12.5
12.0
13.0
12.0
12.5
11.5
12.5
12.0
12.5
12.0
13.0
12.0
12.5
12.0
13.0
11.0
12.0
11.0
12.5
11.0
11.5
11.0
11.5
11.0
12.0
12.0
12.5
11.5
12.5
9.5
10.0
10.0
10.5
11.0
11.5
12.0
12.5
11.0
11.5
11.0
12.0
8.5
3b
3c
3d
3e
3f
3g
3h
3i
10.0
9.0
10.0
11.0
11.5
10.0
10.5
9.5
10.0
9.0
10.0
10.0
10.5
9.0
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
9.5
11.0
11.5
8.5
9.0
10.0
11.0
8.0
9.0
9.5
10.0
12.0
12.5
11.5
12.0
9.5
9.0
9.5
11.5
12.0
11.0
12.0
3u
(continued on next page)

New 4-Aryl-2-amino Thiazoles
2063
TABLE II Antimicrobial Activity Studies of 4-Aryl-2-N-Substituted
Amino Thiozoles (Continued)
Anti-fungal
Antibacterial activity zone
activity zone
diameter (mm)
diameter (mm)
Compound
Concentration µg/ml
BS
SA
EC
PA
CA
4a
100
500
100
500
100
500
100
500
100
500
100
500
100
500
100
500
6.5
7.5
8.0
8.5
7.5
8.5
7.0
8.0
8.0
9.0
7.5
8.0
23.5
28.5
—
7.0
8.0
8.0
8.5
8.0
9.0
7.5
8.5
8.5
9.5
8.0
9.0
10.5
13.5
—
11.0
12.0
11.5
12.0
11.5
12.5
11.0
12.0
11.5
12.0
11.0
12.0
24.0
28.0
—
11.5
12.5
11.0
12.0
11.0
12.0
11.5
12.5
11.0
12.0
11.5
12.0
19.5
23.5
—
10.0
10.5
12.0
12.5
12.0
11.5
10.5
11.0
9.0
4b
4c
5a
5b
5c
CF
FZ
9.5
10.0
11.0
—
—
12.0
13.5
—
—
—
—
by employing 0.5% carboxymethyl cellulose as vehicle. The percent re-
duction in inflammation was calculated with respect to vehicle treated
control values (Table III). All these new molecules exhibit moderate
anti-inflammatory activity.
EXPERIMENTAL
The melting points were uncorrected. CHNSO analysis was done by
Carlo Erba EA 1108 automatic elemental analyzer. I.R Spectra were
1
recorded by Shimadzu FTIR-8108 instrument. H NMR spectra were
recorded on Varian Gemini FT NMR 200 MHz instrument. Mass spectra
were recorded on Hewlett Packard MSEM-5989 spectrometer.
Preparation of New Phenacyl Chlorides
(2a–c)—General Procedure
4-Substituted benzene (50.0 mmol) was added to a stirred mixture
of anhydrous aluminum chloride (60.0 mmol), Bismuth trichloride
3.153 g (10.0 mmol) and chloroacetyl chloride 11.29 g (100.0 mmol) in
Dichloromethane (125 ml) at 0–5◦C. The reaction mass was stirred at
0–5◦C for 3–4 h. After the reaction was over, it was poured into ice-cold

2064
T. Giridhar et al.
TABLE III Anti-inflammatory Activity
S. no.
Compound Dose mg/kg/po
Inhibition (%)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
3a
3b
3c
3d
3e
3f
3g
3h
3i
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
21
20
30
12
18
16
20
24
33
16
12
15
—
31
15
26
19
—
18
11
—
30
32
35
40
41
48
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
3u
4a
4b
4c
5a
5b
5c
water to decompose in aluminum chloride. The organic layer was sepa-
rated and dichloromethane was completely distilled off under vacuum
to get the corresponding phenacyl chloride.
4-(N-butyl) Phenacyl Chloride (2a)
86%. (Found: C, 68.41; H, 7.12; Cl, 16.85%. C12H15OCl requires C,
68.40; H, 7.12; Cl, 16.86%). IR (KBr, cm−1): 1701–1685(C O), 1605,
(C C). PMR (CDCl3,δ ppm): 7.85 (d, 2H, Ar-H ortho to C O), 7.25 (d,
2H, Ar-H meta to C O), 4.7 (s, 2H, COCH2), 2.6–2.7 (t, 2H, benzylic),
1.5–1.7 (m, 2H, -CH2), 1.2–1.5 (m, 2H, -CH2), 0.85–1.0 (t, 3H, CH3).
Mass (m/z): 210(M+; 3), 161 (M-CH2Cl, 100), 133 (161-CO, 9).
4-(Isobutyl) Phenacyl Chloride (2b)
87%. (Found: C, 68.42; H, 7.11; Cl, 16.87%. C12H15OCl requires C,
68.40; H, 7.12; Cl, 16.86%). IR (KBr, cm−1): 1701–1685(C O), 1605,
(C C). PMR (CDCl3,δ ppm): 7.9 (d, 2H, Ar-H ortho to C O), 7.3

New 4-Aryl-2-amino Thiazoles
2065
(d, 2H, Ar-H meta to C O), 4.7 (S, 2H, COCH2), 2.5–2.6 (d, 2H, ben-
zylic), 1.8–2.0 (m, 1H, -CH(CH3)2, 0.9–1.0 (d, 6H, -CH3). Mass (m/z):
210(M+; 3), 167 (M- C3H7, 3) 161 (M-CH2Cl, 100), 133 (161-CO, 10).
4-(Ter-butyl) Phenacyl Chloride (2c)
92%. (Found: C, 68.39; H, 7.13; Cl, 16.87% C12H15OCl requires C,
68.40; H, 7.12; Cl, 16.86%). IR (KBr, cm−1): 1701–1685(C O), 1605,
(C C). PMR (CDCl3,δ ppm): 7.9 (d, 2H, Ar-H ortho to C O), 7.5 (d,
2H, Ar-H meta to C O), 4.7 (s, 2H, COCH2), 1.35 (s, 9H, CH3). Mass
(m/z): 210(M+; 2), 195 (M- CH3, 15), 161 (M-CH2Cl, 100), 146(161- CH3,
15), 133(161-CO, 5).
Preparation of 2-Amino-4-Aryl Thiazole Derivatives (3a-u):
General Procedure
Thiourea 3.80 6g (50.0 mmol), phenacyl chloride (50.0 mmol) along with
BiCl3 3.153 g (10.0 mmol) and 60 ml of Dichloromethane was charged
and the reaction mixture was stirred for an additional 30 min at the
same temperature. The temperature was raised to reflux, and the reac-
tion mixture was maintained at reflux for 1 to 2 h. Then, it was cooled to
ambient temperature and poured into ice-cold water. The product was
then separated by ether extraction and evaporation. The product was
washed with 10% sodium hydroxide solution followed by water until
washing were neutral to PH and then dried. The product were recrys-
tallized from aqueous methanol.
2-Amino-4-/(4-N-butyl) Phenyl/Thiazole (3a)
(68%), m.p. 234–238◦C. (Found C, 67.27; H, 6.90; N, 12.07; S, 13.77%.
C13H16N2S requires C, 67.24; H, 6.89; N, 12.06; S, 13.79%). (IR cm−1):
3363–3069 (NH), 1640–1620 (C C, C N), 1575, 1560. PMR (CDCl3, δ
ppm): 8.5–9.3 (br, s, 2H, NH2), 7.7 (d, 2H, Ar-H, ortho to thiazole), 7.30
(d, 2H, ortho to butyl), 7.2 (s, 1H, thiazole-H), 2.6–2.8 (t, 2H, benzylic),
1.5–1.7 (m, 2H, CH2), 1.25–1.45 (m, 2H, CH2), 0.8–1.0 (t, 3H, CH3).
Mass (m/z): 232 (M+; 68), 203 (M-C2H5, 4), 189 (M-C3H7, 100).
2-Amino-4-/(4-Iso-butyl) Phenyl/Thiazole (3b)
(90%), m.p. 112%116◦C. (Found C, 67.25; H, 6.90; N, 12.03; S, 13.76%.
C13H16N2S requires C, 67.24; H, 6.89; N, 12.06; S, 13.79%). (IR cm−1):
3313–3107, 1630, 1598, and 1536. PMR (CDCl3, δ ppm): 5.2–5.4 (br,
s, 2H, NH2), 7.7 (d, 2H, Ar-H, ortho to thiazole), 7.20 (d, 2H, ortho
to iso butyl), 6.7 (s, 1H, thiazole-H), 2.5 (d, 2H, benzylic), 1.8 (m, 1H,
CH(CH3)2), 0.9 (d, 6H, CH3). Mass (m/z): 232 (M+; 47), 217 (M-CH3,
40), 203 (M-C2H5, 4), 189 (M-C3H7, 100), 147 (189-NCN H2, 13).

2066
T. Giridhar et al.
2-Amino-4-/(4-Ter-butyl) Phenyl/Thiazole (3c)
(97%), m.p. 228–230◦C. (Found C, 67.26; H, 6.89; N, 12.0; S, 13.77%.
C13H16N2S requires C, 67.24; H, 6.89; N, 12.06; S, 13.79%). (IR cm−1):
3450–3100, 1628, 1606, 1570, 1530. PMR (DMSO-d6, δ ppm): 8.2–
8.6 (br, s, 2H, NH2 disappeared with D2O), 7.7 (d, 2H, Ar-H, ortho to
thiazole), 7.45 (d, 2H, ortho to ter-butyl), 7.1 (s, 1H, thiazole-H), 1.3 (s,
9H, CH3). Mass (m/z): 232 (M+; 60), 217 (M-CH3, 100), 175 (M-C4H9,
5), 142 (217-HNCSNH2, 15).
4-/(4-N-butyl) Phenyl/-2-(N-methyl Amino) Thiazole (3d)
(58%), m.p. 93–95◦C. (Found C, 68.31; H, 7.30; N, 11.39; S, 12.98%.
C14H18N2S requires C, 68.29; H, 7.31; N, 11.38; S, 13.00%). IR (cm−1):
3210–3190, 1589, 1570, and 1491. PMR (CDCl3, δ ppm): 7.7 (d, 2H,
Ar-H ortho to thiazole), 7.2 (d, 2H, Ar-H ortho to butyl), 6.65(s, 1H,
thiazole-H), 6.15 (br, s, 1H, NH), 2.95(s, 3H, N-CH3), 2.65(t, 2H, ben-
zylic), 1.5–1.7(m, 2H, CH2), 1.3–1.5(m, 2H, CH2), 0.9–1.0(t, 3H, CH3),
Mass (m/z): 246(M+; 72), 218 (M-C2H4, 8), 203(M-C3H7, 100), 147
(203-NCNHCH3, 8).
4-/(4-Iso-butyl) Phenyl/-2-(N-methyl Amino) Thiazole (3e)
(78%), m.p. 118–119◦C. (Found C, 68.27; H, 7.33; N, 11.36; S, 13.02%.
C14H18N2S requires C, 68.29; H, 7.31; N, 11.38; S, 13.00%). IR (cm−1):
3268, 1581, 1570, 1492, 1465. PMR (CDCl3, δ ppm): 7.7 (d, 2H, Ar-
H ortho to thiazole), 7.15 (d, 2H, Ar-H ortho to isobutyl), 6.65(s, 1H,
thiazole-H), 6.0 (br, s, 1H, NH), 2.95(s, 3H, N-CH3), 2.5(d, 2H, benzylic),
1.8–2.0(m, 1H, -CH (CH3)2), 0.95(d, 6H, CH3), Mass (m/z): 246(M+; 74),
203 (M-C3H7, 100), 174(203-HCN,H2, 3), 149(203-NCNCH2, 5).
4-/(4-Ter-butyl) Phenyl/-2-(N-methyl Amino) Thiazole (3f)
(81%), m.p. 124–128◦C. (Found C, 68.27; H, 7.33; N, 11.37; S, 13.01%.
C14H18N2S requires C, 68.29; H, 7.31; N, 11.38; S, 13.00%). IR (cm−1):
3214–3130, 1587, 1566, 1507, 1491. PMR (CDCl3, δ ppm): 7.75 (d, 2H,
Ar-H ortho to thiazole), 7.4 (d, 2H, Ar-H ortho to ter-butyl), 6.65(s, 1H,
thiazole-H), 5.75 (br, s, 1H, NH), 3.0(s, 3H, N-CH3), 1.35(s, 9H, CH3),
Mass (m/z): 246(M+; 72), 231(M-CH3,100), 216 (M-C2H6, 8), 203(M-
C3H7, 16), 190(M-C4H8, 9).
4-/(4-N-butyl) Phenyl/-2-(N-phenyl Amino) Thiazole (3g)
(52%), m.p. 162–166◦C. (Found C, 74.01; H, 6.48; N, 9.08; S, 10.39%.
C19H20N2S requires C, 74.02; H, 6.49; N, 9.09; S, 10.38%). IR (cm−1):
3242–3188, 1620, 1604, 1578, 1498. PMR (CDCl3, δ ppm): 7.75 (d,
2H, H-7, H-11), 7.45 (m, 5H, N-C6H5), 7.1–7.3(d, 2H, H-8, H-10, 1H,

New 4-Aryl-2-amino Thiazoles
2067
thiazole-H), 6.7 (s, 1H, NH disappeared with D2O), 2.65(t, 2H, CH2),
1.65(m, 2H,CH2), 1.35(m, 2H, CH2), 0.95(t, 3H, CH3), Mass (m/z): 308
(M+; 100), 265 (M-C3H7, 71), 187(265-C6H6, 3).
4-/(4-Iso-butyl) Phenyl/-2-(N-phenyl Amino) Thiazole (3h)
(58%), m.p. 169–173◦C. (Found C, 74.00; H, 6.47; N, 9.10; S, 10.36%.
C19H20N2S requires C, 74.02; H, 6.49; N, 9.09; S, 10.38%). IR (cm−1):
3244–3042, 1623, 1592, 1567, 1499. PMR (CDCl3, δ ppm): 7.75 (d, 2H,
H-7, H-11), 7.45 (m, 5H, N-C6H5), 7.25 (d, 2H, H-8, H-10, 1H, thiazole-
H), 6.65 (s, 1H, NH disappeared with D2O), 2.55(d, 2H, CH2), 1.9(m, 1H,
-CH(CH3)2), 0.95(d, 6H, CH3), Mass (m/z): 308 (M+; 89), 265 (M-C3H7,
100).
4-/(4-Ter-butyl) Phenyl/-2-(N-phenyl Amino) Thiazole (3i)
(60%), m.p. 136–140◦C. (Found C, 74.01; H, 6.48; N, 9.09; S, 10.39%.
C19H20N2S requires C, 74.02; H, 6.49; N, 9.09; S, 10.38%). IR (cm−1):
3208–3111, 1589, 1561, 1496. PMR (CDCl3, δ ppm): 7.8 (d, 2H, H-7, H-
11), 7.4 (m, 5H, N-C6H5, and 2H, H-8, H-10, 1H, thiazole-H), 6.8 (s, 1H,
thiazole-H), 1.35(s, 9H, CH3), Mass (m/z): 308 (M+; 98), 293 (M-CH3,
100), 265 (293-C2H4, 12), 251 (M-C4H9, 5).
4-/(4-N-butyl) Phenyl/-2-(N-benzyl Amino) Thiazole (3j)
(68%), m.p. 120–122◦C. (Found C, 74.55; H, 6.81; N, 8.67; S, 9.91%.
C20H22N2S requires C, 74.53; H, 6.83; N, 8.69; S, 9.93%). IR (cm−1):
3242–3188, 1620, 1604, 1579, 1443. PMR (CDCl3, δ ppm): 7.65 (d,
2H, H-7, H-11), 7.4 (s, 5H, N-C6H5), 7.25 (d, 2H, H-8, H-10), 6.5 (s,
1H, thiazole-H), 10.35 (s, 1H, NH disappeared with D2O), 4.55 (d, 2H,
NHCH2, coalesced to singlet with D2O exchange) 2.65(t, 2H, CH2, ben-
zylic), 1.6 (m, 2H,CH2), 1.35(m, 2H, CH2), 0.95(t, 3H, CH3), Mass (m/z):
322 (M+; 74), 279 (M-C3H7, 10), 218(M-C6H5CN,H, 16), 91(C7H7, 100).
4-/(4-Iso-butyl) Phenyl/-2-(N-benzyl Amino) Thiazole (3k)
(57%), m.p. 113–116◦C. (Found C, 74.51; H, 6.83; N, 8.68; S, 9.95%.
C20H22N2S requires C, 74.53; H, 6.83; N, 8.69; S, 9.93%). IR (cm−1):
3244–3042, 1623, 1592, 1567, 1499. PMR (CDCl3, δ ppm): 7.7 (d, 2H,
H-7, H-11), 7.35 (s, 5H, N-C6H5), 7.1 (d, 2H, H-8, H-10), 6.65 (s, 1H,
thiazole-H), 5.8 (br, 1H, NH disappeared with D2O), 4.5 (d, 2H, NHCH2,
coalesced to singlet with D2O exchange) 2.5(d, 2H, CH2, benzylic), 1.9
(m, 1H,CH(CH3)2), 0.95 (d, 6H, CH3), Mass (m/z): 322 (M+; 74), 279
(M-C3H7, 10), 218(M-C6H5CN, H, 16), 91(C7H7, 100).

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4-/(4-Ter-butyl) Phenyl/-2-(N-benzyl Amino) Thiazole (3l)
(65%), m.p. 173–176◦C. (Found C, 74.52; H, 6.84; N, 8.68; S, 9.94%.
C20H22N2S requires C, 74.53; H, 6.83; N, 8.69; S, 9.93%). IR (cm−1):
3208–3111, 1589, 1561, 1496. PMR (CDCl3, δ ppm): 7.8 (d, 2H, H-7,
H-11), 7.1 (s, 5H, -C6H5), 7.3 (d, 2H, H-8, H-10), 6.7 (s, 1H, thiazole-H),
5.6 (br, 1H, NH disappeared with D2O), 2.3 (d, 2H, coalesced to singlet
with D2O exchange) 1.4 (s, 9H, CH3). Mass (m/z): 322 (M+; 28), 265
(M-C4H9, 10), 91(C7H7, 100).
4-/(4-N-butyl) Phenyl/-2-/N- (2-Phenyl) Ethyl Amino/
Thiazole (3m)
(70%), m.p. 126–129◦C. (Found C, 74.97; H, 7.15; N, 8.31; S, 9.5%.
C21H24N2S requires C, 74.99; H, 7.14; N, 8.33; S, 9.52%). IR (cm−1):
3204–3125, 1591, 1493. PMR (CDCl3, δ ppm): 7.7 (d, 2H, H-7, H-
11), 7.1–7.4 (m, 5H, N-C6H5, and 2H, H-8, H-10), 6.65 (s, 1H, thiazole-
H), 5.4 (br, s, 1H, NH disappeared with D2O), 3.55 (q, 2H, NHCH2,
coalesced to triplet with D2O exchange), 3.0 (t, 2H, NCH2CH2), 2.65
(t, 2H, CH2,benzylic), 1.65 (m, 2H,CH2), 1.35(m, 2H, CH2), 0.95(t, 3H,
CH3), Mass (m/z): 336 (M+; 54), 245 (M-C7H7, 100), 232(M-C8H8, 94),
189(245-C4H8, 40).
4-/(4-Iso-butyl) Phenyl/-2-/N- (2-Phenyl) Ethyl Amino/
Thiazole (3n)
(60%), m.p. 107–109◦C. (Found C, 75.01; H, 7.13; N, 8.35; S, 9.54%.
C21H24N2S requires C, 74.99; H, 7.14; N, 8.33; S, 9.52%). IR (cm−1):
3208, 1583, 1570, 1508, 1495. PMR (CDCl3, δ ppm): 7.7 (d, 2H, H-7,
H-11), 7.1–7.4 (m, 5H, C6H5, and 2H, H-8, H-10), 6.65 (s, 1H, thiazole-
H), 5.9 (br, s, 1H, NH disappeared with D2O), 3.6 (t, 2H, NHCH2), 3.0
(t, 2H, NCH2CH2), 2.5 (d, 2H, CH2, benzylic), 1.9 (m, 1H,CH(CH3)2),
0.95(d, 6H, CH3). Mass (m/z): 336 (M+; 62), 293 (M-C3H7, 12), 245(M-
C7H7, 96), 232(M-C8H8, 100), 189(245-C4H8, 45).
4-/(4-Ter-butyl) Phenyl/-2-/N- (2-Phenyl) Ethyl Amino/
Thiazole (3o)
(54%), m.p. 147–149◦C. (Found C, 74.96; H, 7.12; N, 8.35; S, 9.55%.
C21H24N2S requires C, 74.99; H, 7.14; N, 8.33; S, 9.52%). IR (cm−1):
3211, 1587, 1495, and 1473. PMR (CDCl3, δ ppm): 7.8 (d, 2H, H-7, H-
11), 7.4 (d, 2H, H-8, H-10), 7.2–7.3 (m, 5H, C6H5), 6.7 (s, 1H, thiazole-H),
5.5 (br, s, 1H, NH disappeared with D2O), 3.6 (q, 2H, NHCH2, coalesced
to triplet with D2O exchange), 3.0 (t, 2H, NCH2CH2), 1.4(s, 9H, CH3).
Mass (m/z): 336 (M+; 64), 321(M-CH3, 10), 245 (M-C7H7, 73), 232(M-
C8H8, 100), 189(245-C4H8, 43).

New 4-Aryl-2-amino Thiazoles
2069
4-/(4-N-butyl) Phenyl/-2-/N- (2-(4-Methoxyphenyl) Ethyl)
Amino/Thiazole (3p)
(77%), m.p. 108–110◦C. (Found C, 72.15; H, 7.11; N, 7.62; S, 8.76%.
C22H26N2OS requires C, 72.13; H, 7.10; N, 7.65; S, 8.74%). IR (cm−1):
3208, 1610, 1591, 1512, and 1491. PMR (CDCl3, δ ppm): 7.8 (d, 2H,
H-7, H-11), 6.9 (d, 2H, H-8, H-10), 7.1–7.3(m, 4H,H-18, H-19, H-21 and
H-22), 6.65 (s, 1H, thiazole-H), 5.6 (br, s, 1H, NH disappeared with
D2O), 3.8 (s, 3H, OCH3), 3.55 (q, 2H, NHCH2, coalesced to triplet with
D2O exchange), 2.95 (t, 2H, NCH2CH2), 2.65 (t, 2H, benzylic), 1.65 (m,
2H,CH2), 1.4(m, 2H, CH2), 1.0(t, 3H, CH3), Mass (m/z): 336 (M+; 10),
245 (M-C8H9O, 100), 232(M-C9H10O, 100), 189(245-C4H8, 28).
4-/(4-Iso-butyl) Phenyl/-2-/N- (2-(4-Methoxyphenyl) Ethyl)
Amino/Thiazole (3q)
(54%), m.p. 95–98◦C. (Found C, 72.11; H, 7.09; N, 7.66; S, 8.72%.
C22H26N2OS requires C, 72.13; H, 7.10; N, 7.65; S, 8.74%). IR (cm−1):
3383, 3208, 1612, 1585, 1556, 1512, 1491. PMR (CDCl3, δ ppm): 7.7
(d, 2H, H-7, H-11), 6.85 (d, 2H, H-8, H-10), 7.1–7.2(m, 4H,H-18, H-19,
H-21 and H-22), 6.65 (s, 1H, thiazole-H), 5.45 (br, s, 1H, NH disappeared
with D2O), 3.8 (s, 3H, OCH3), 3.5 (q, 2H, NHCH2, coalesced to triplet
with D2O exchange), 2.95 (t, 2H, NCH2CH2), 2.6 (t, 2H, benzylic),1.9
(m,1H, CH(CH3)2), 0.95 (d, 6H, CH3), Mass (m/z): 336 (M+; 10), 245
(M-C8H9O, 17), 232 (M-C9H10O, 100), 189(245-C4H8, 35).
4-/(4-Ter-butyl) Phenyl/-2-/N- (2-(4-Methoxyphenyl) Ethyl)
Amino/Thiazole (3r)
(62%), m.p. 124–127◦C. (Found C, 72.10; H, 7.13; N, 7.67; S, 8.75%.
C22H26N2OS requires C, 72.13; H, 7.10; N, 7.65; S, 8.74%). IR (cm−1):
3285, 1612, 1564, 1512, and 1489. PMR (CDCl3, δ ppm): 7.8 (d, 2H,
H-7, H-11), 7.4 (d, 2H, H-8, H-10), 7.1(d, 2H, H-19, H-21), 6.9 (d, 2H,
H-18, H-22), 6.7 (s, 1H, thiazole-H), 5.7 (br, s, 1H, NH disappeared with
D2O), 3.8 (s, 3H, OCH3), 3.5 (q, 2H, NHCH2, coalesced to triplet with
D2O exchange), 2.9 (t, 2H, NCH2CH2), 1.4 (s, 9H, CH3), Mass (m/z):
336 (M+; 10), 245 (M-C8H9O, 10), 232 (M-C9H10O, 100), 189(245-C4H8,
15).
4-/(4-n-Butyl) Phenyl/-2- (N-Acetyl Amino) Thiazole (3s)
(51%), m.p. 191–193◦C. (Found C, 65.65; H, 6.55; N, 10.22; S, 11.7%.
C15H18N2OS requires C, 65.69; H, 6.56; N, 10.21; S, 11.67%). IR (cm−1):
3237 (NH), 1654 (C O), 1575, 1557, and 1490. PMR (CDCl3, δ ppm):
7.7 (d, 2H, Ar-H ortho to thiazole), 7.3 (d, 2H, Ar-H ortho to n-butyl), 6.8
(s, 1H, thiazole-H), 6.4 (br, s, 1H, NH, disappeared with D2O exchange),

2070
T. Giridhar et al.
2.65 (t, 2H, n-butyl), 1.65 (m, 2H, n-butyl), 2.1(s, 3H, COCH3), 1.4 (m,
2H, n-butyl) 1.1 (s, 3H, n-butyl). Mass (m/z): 274(M+; 43), 217 (M-C4H9,
18), 202 (217-CH3, 48).
4-/(4-Iso-butyl) Phenyl/-2- (N-acetyl Amino) Thiazole (3t)
(55%), m.p. 189–192◦C. (Found C, 65.71; H, 6.58; N, 10.20; S, 11.65%.
C15H18N2OS requires C, 65.69; H, 6.56; N, 10.21; S, 11.67%). IR (cm−1):
3237 (NH), 1654 (C O), 1575, 1557, 1490. PMR (CDCl3, δ ppm): 7.8
(d, 2H, Ar-H ortho to thiazole), 7.2 (d, 2H, Ar-H ortho to isobutyl), 7.1(s,
1H, thiazole-H), 11.8 (br, s, 1H, NH), 2.5(d, 2H, benzylic), 1.9(m, 1H,
CH), 1.75 (s, 3H, COCH3), 0.9(d, 6H, CH3), Mass (m/z): 274(M+; 52),
232 (M-CH2CO, 78), 189(232-C3H7, 100), 147(189-NCNCH2, 17).
4-/(4-Ter-butyl) Phenyl/-2-(N-acetyl Amino) Thiazole (3u)
(64%), m.p. 232–235◦C. (Found C, 65.67; H, 6.54; N, 10.19; S, 11.68%.
C15H18N2OS requires C, 65.69; H, 6.56; N, 10.21; S, 11.67%). IR (cm−1):
3230 (NH), 1660 (C O), 1571, 1556, and 1491. PMR (DMSO-d6,δ
ppm): 7.8 (d, 2H, Ar-H ortho to thiazole), 7.4 (d, 2H, Ar-H ortho to ter-
butyl), 7.1(s, 1H, thiazole-H), 11.2–11.6 (br, s, 1H, NH disappeared with
D2O), 1.8 (d, 3H, COCH3 coalesced to a singlet with D2O exchange), 1.4
(s, 9H, CH3), Mass (m/z): 274(M+; 62), 259(M-CH3, 22), 232 (M-CH2CO,
69), 217(232-CH3 or M-C4H9, 100), 189(217-CO, 12).
4-/(4-N-butyl)/Phenyl/- 2-(Diamino Methyleneimino) Thiazole
(4a)
(42%), m.p. 256–258◦C. (Found C, 61.33; H, 6.57; N, 20.41; S, 11.65%.
C14H18N4S requires C, 61.31; H, 6.56; N, 20.43; S, 11.67%). (IR cm−1):
3425–3116, 1657, 1649, 1599, 1549, and 1484. PMR (CDCl3+DMSO-
d6, δ ppm): 7.7 (d, 2H, Ar-H, ortho to thiazole), 7.2 (d, 2H,Ar-H, ortho to
n-butyl), 6.75 (s, 1H, thiazole-H), 6.0–7.0 (br, s, 4H, NH2, disappeared
with D2O), 2.65 (t, 2H, benzylic), 1.6(m, 2H, H-13), 1.35 (m, 2H, H-14),
0.95 (t, 3H, CH3). Mass (m/z): 274 (M+; 100), 257 (M-NH3,61), 232 (M-
C3H6 or M-NCNH2, 27), 214 (257-C3H7, 80), 189 (232-C3H7, 60) 147
(189-NCNH2, 29).
4-/(4-Iso-butyl) Phenyl/-2-(Diamino Methyleneimino)
Thiazole (4b)
(35%), m.p. 238–240◦C. (Found C, 61.29; H, 6.56; N, 20.41; S, 11.68%.
C14H18N4S requires C, 61.31; H, 6.56; N, 20.43; S, 11.67%). (IR cm−1):
3440–3172, 1601, 1649, 1536, 1500, and 1460. PMR (DMSO-d6, δ
ppm): 7.75 (d, 2H, Ar-H, ortho to thiazole), 7.2 (d, 2H, Ar-H, ortho
to Isobutyl), 7.05 (s, 1H, thiazole H), 6.8–7.0 (br, s, 4H, NH2, disap-
peared with D2O), 2.45 (d, 2H, benzylic), 1.82–2.0(m, 1H, CH(CH3)2),

New 4-Aryl-2-amino Thiazoles
2071
0.9 (d, 6H, CH3). Mass (m/z): 274 (M+; 43), 257 (M-NH3,17), 232 (M-
C3H6 or M-NCNH2, 44), 189 (232-C3H7, 100), 147 (189-NCNH2, 19).
4-/(4-Ter-butyl) Phenyl/-2-(Diamino Methyleneimino)
Thiazole (4c)
(35%), m.p. 242–243◦C. (Found C, 61.30; H, 6.57; N, 20.41; S, 11.68%.
C14H18N4S requires C, 61.31; H, 6.56; N, 20.43; S, 11.67%). (IR cm−1):
3445–3435, 1599, 1649, 1558, and 1497. PMR (CDCl3, δ ppm): 7.80
(d, 2H, Ar-H, ortho to thiazole), 7.45 (d, 2H, Ar-H, ortho to terbutyl),
7.15 (s, 1H, thiazole-H), 6.95–7.15 (br, s, 4H, NH2, disappeared with
D2O), 1.35 (s, 9H, CH3). Mass (m/z): 274 (M+; 65), 257 (M-NH3,20),
242 (257-CH3), 232 (M-C3H6 or M-NCNH2, 59), 217 (M-C4H9, 100), 189
(232-NCNH2, H, 18) 175 (232-C4H9, 15).
4-/(4-N-butyl) Phenyl/-2–(N-methyl-N-acetyl Amino)
Thiazole (5a)
(41%), m.p. 119–121◦C. (Found C, 66.70; H, 6.95; N, 9.70; S, 11.09%.
C16H20N2OS requires C, 66.66; H, 6.94; N, 9.72; S, 11.11%). (IR cm−1):
3115 (CH), 1663 (C O), 1542, and 1491. PMR (CDCl3, δ ppm): 7.80
(d, 2H, Ar-H, ortho to thiazole), 7.20 (d, 2H, ortho to ter butyl), 7.1 (s,
1H, thiazole-H), 3.8 (s, 3H, NCH3), 2.65 (t, 2H, benzylic), 2.4 (s, 3H,
COCH3), 1.6 (m, 2H, CH2), 1.4(m, 2H, -CH2-), 0.9 (t, 3H, CH3). Mass
(m/z): 288 (M+; 39), 246 (M-CH2CO, 100), 203 (246-C3H7, 77).
4-/(4-Iso-butyl) Phenyl/-2–(N-methyl-N-acetyl Amino)
Thiazole (5b)
(38%), m.p. 130–132◦C. (Found C, 66.63; H, 6.92; N, 9.75; S, 11.14%.
C16H20N2OS requires C, 66.66; H, 6.94; N, 9.72; S, 11.11%). (IR cm−1):
3108 (CH), 1670 (C O), 1536, and 1493. PMR (CDCl3, δ ppm): 7.80 (d,
2H, Ar-H, ortho to thiazole), 7.20 (d, 2H, ortho to ter butyl), 7.1 (s, 1H,
thiazole-H), 3.8 (s, 3H, NCH3), 2.5 (d, 2H, benzylic), 2.4 (s, 3H, COCH3),
1.9 (m, 1H, CH(CH3)2), 0.9 (d, 6H, CH3). Mass (m/z): 289 (MH+, 42),
288 (M+; 47), 246 (M-CH2CO, 97), 203 (246-C3H7, 100).
4-/(4-Ter-butyl) Phenyl/-2–(N-methyl-N-acetyl Amino)
Thiazole (5c)
(52%), m.p. 120–122◦C. (Found C, 66.68; H, 6.97; N, 9.71; S, 11.13%.
C16H20N2OS requires C, 66.66; H, 6.94; N, 9.72; S, 11.11%). (IR cm−1):
3112 (CH), 1668 (C O), 1536, and 1493. PMR (CDCl3, δ ppm): 7.80
(d, 2H, Ar-H, ortho to thiazole), 7.50 (d, 2H, ortho to ter butyl), 7.1 (s,
1H, thiazole-H), 3.8 (s, 3H, NCH3), 2.4 (s, 3H, COCH3), 1.4 (s, 9H, CH3).
Mass (m/z): 288 (M+; 37), 246 (M-CH2CO, 89), 231 (M-C4H9, 100).

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