Novel synthetic approach to N-aryl-4-(3-pyridyl)thiazol-2-amine and analogues using HMCM-41 as catalyst, and their biological evaluation as human platelet aggregation inhibitors

Article abstract of DOI:10.1016/j.ejmech.2007.01.016

A novel synthetic approach to N-aryl-4-(3-pyridyl)thiazol-2-amine and analogues using HMCM-41, a mesoporous aluminosilicate catalyst and their in vitro ADP-induced platelet aggregation inhibitory activity on human blood platelets is described. Among the test compounds N-(2′-flourophenyl)-4-(3-pyridyl)thiazol-2-amine (9e) was found to be the most potent, IC₅₀ = 4.84 × 10^-7 M.

Full text of DOI:10.1016/j.ejmech.2007.01.016

European Journal of Medicinal Chemistry 42 (2007) 1144e1150
http://www.elsevier.com/locate/ejmech
Short communication
Novel synthetic approach to N-aryl-4-(3-pyridyl)thiazol-2-amine
and analogues using HMCM-41 as catalyst, and their biological
evaluation as human platelet aggregation inhibitors
Umadevi Bhoga
Organic Division, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Received 14 June 2006; received in revised form 3 January 2007; accepted 15 January 2007
Available online 27 January 2007
Abstract
A novel synthetic approach to N-aryl-4-(3-pyridyl)thiazol-2-amine and analogues using HMCM-41, a mesoporous aluminosilicate catalyst
and their in vitro ADP-induced platelet aggregation inhibitory activity on human blood platelets is described. Among the test compounds N-(20-
flourophenyl)-4-(3-pyridyl)thiazol-2-amine (9e) was found to be the most potent, IC50 ¼ 4.84 ꢀ 10ꢁ7 M.
Ó 2007 Published by Elsevier Masson SAS.
Keywords: N-Aryl-4-(3-pyridyl)thiazol-2-amine and analogues; HMCM-41; Antiplatelet aggregation activity
1. Introduction
investigated for their application to ischemic disease. In
addition, there are a few ADP-induced platelet aggregation an-
tagonists such as clopidogrel [19], 4-(4-amidinophenoxy)
butanoyl aspartyl valine monohydrate [20], isoflurane [21]
and propofol [22], 2-[4-[N-(5,6-diphenyl pyrazin-2-yl)-N-
methylamino]-butoxy] acetic acid [23], N-(6-ethoxybenzo
thiazol-2-yl)-2-(8-ethoxy-4-hydroxy-2,2-dioxo[1,2,4]thia-
diazino[3,4-b]benzothiazol-3-yl)-2-oxoethane-1-sulfonamide
[24], cis-3-(3,5-diflourophenyl)-2-(4-flourophenyl-4-hydroxy-5-
methyl-4-phenyl-2-cyclopenten-1-one isomer A [25], P1-[N6-[N-
(4-flourophenyl)carbamoyl]-20-O,30-O-(2-phenylethylidene)
cytidin-50-yl]-P4-[20-O,30-(2-phenylethylidene) uridin-50-yl]-
tetra phosphate [26], 2(S )-(methoxalylamino)-3-[1-[3-
(4-piperidinyl)propionyl]-piperidin-3(R)-yl-carboxamido]
propionic acid [27], 1-[4-(6-ethylthieno[2,3-d]pyrimidin-4-
yl)piperazin-1-yl]-2-phenyl ethanone triflouro acetate [28].
Among them, aspirin has been studied most extensively. How-
ever, due to irreversible inhibition of cyclooxygenase, aspirin in-
hibits not only synthesis of thromboxane A2 (TXA) in platelets,
but also prostaglandin I2 in vascular endothelial cells and as a
result, aspirin induces stomach ulcers [29]. Keeping pharmaceu-
tical potential of 2-(20-flourophenyl)-5-methyl-4-(3-pyridyl)-
imidazole 5 and 6ael series in view as most potent antiplatelet
Platelets play a major role in development of thromboem-
bolic disease [1], myocardial infarction, stroke, unstable an-
gina [2], cardiovascular diseases [3], and ischemic disease
[4]. Till date, several compounds possessing platelet aggrega-
tion inhibitory activity have been discovered [5]. To the best of
our knowledge, aspirine 1 [6], E-5510 2 [7], iloprost 3 [8], CV-
4151 4 [9], 2-(20-fluorophenyl)-5-methyl-4-(3-pyridyl)imida-
zole 5 [10], 6ael series [11] and (amino benzamidino) succinyl
(ABAS) series of orally active fibrinogen receptor antago-
nists [12], abciximab, a humanemouse monoclonal antibody
for intravenous infusion, binding to glycoprotein IIb/IIIa
receptor on human platelets [13] are a few (Fig. 1). However,
the mechanism of drugs on inhibition varies based on the
inhibitory capability of a particular enzyme [14]. For example,
aspirin 1 inhibits cyclooxygenase [15], ozagrel inhibits throm-
boxane synthetase [16], ticlopidine activates adenylate cyclase
[17], dipyridamoles and cilostazole inhibit phosphodiesterase
[18] and the above-mentioned compounds have been
E-mail address: ubhoga@yahoo.co.in
0223-5234/$ - see front matter Ó 2007 Published by Elsevier Masson SAS.
doi:10.1016/j.ejmech.2007.01.016

U. Bhoga / European Journal of Medicinal Chemistry 42 (2007) 1144e1150
1145
H3CO
aggregation agents, it was planned to design new chemical enti-
ties with similar skeletal backbone i.e., pyridyl ring at 4-position
of the thiazole system and various aryl, naphthyl and benzyl
substituents on 2-amino group of the thiazole ring in order to
unravel their ADP-induced antiplatelet aggregation activity on
human blood platelets.
COOH
OCOCH3
CN
CH2CH2COOH
1
H3CO
2
COOH
N
2. Chemistry
H
CH2CH2CH2CH2COOH
In the present approach, N-aryl-4-(3-pyridyl)thiazol-2-amine
and analogues 9aej were obtained by HMCM-41 catalyzed cyclo-
condensation of 3-(a-bromo)-acetylpyridine hydrobromide (7)
and N-arylthioureas 8aej based on well known Hantzsch-thiazole
synthesis [30]. 3-(a-Bromo)-acetylpyridine hydrobromide (7) was
obtained by bromination of 3-acetylpyridine using bromine and
hydrobromic acid in acetic acid [31]. N-Arylthioureas 9aeg, N-
naphthylthiourea 9i and N-benzylthiourea 9h were prepared by
treatment of an equimolar proportions of commercially available
primary arylamines, 1-naphthylamine and benzylamine, respec-
tively, with ammonium thiocyanate in 15% of the aqueous hydro-
chloric acid at 100 ꢂC[32]. The condensation catalyst, HMCM-41,
an acidic mesoporous crystalline aluminosilicate has unique phys-
ical properties which made these materials highly efficient for cat-
alytic applications [33]. The high specific surface area is
conductive to high catalytic activity. The large pore size of the cav-
ities allows the fixation of large reactants, thus enables reaction in-
volving bulky groups to take place, i.e., shape selectivity. Being
acidic in nature, HMCM-41 protonates the carbonyl group of 3-
(a-bromo)-acetylpyridine, resulting in an ionic intermediatewhich
on nucleophilic attack by amino group of arylthiourea followed by
loss of HMCM-41, dehydrobromination and dehydration in cyclo-
condensation furnish 2-amino-4-(3-pyridyl)-thiazole analogues
9aej. Depicted mechanism is given below [33f].
CH3
CH3
HO
HO
4
3
A
R
N
COOH
N
S
H
N
N
N
N
H2N
NH
CH3
F
6a-l
5
6g R = H; A = CH(2-ClC6H4)
6h R = CH3; A = CH2
6i R = CH2C6H5; A = CH2
6j R = CH2COOH; A = CH2
6k R = (CH2)2COOH; A = CH2
6l R = (CH2)3COOH; A = CH2
6a R = H; A = CH2
6b R = H; A = CHCH3
6c R = H; A = C(CH3)2
6d R = H; A = CHCH2COOH
6e R = H; A = CHC6H5
6f R = H; A = CH2CH2
Fig. 1.
Mechanism
O
OH
Br
Br
HMCM-41
N
.
N
.
HBr
MCM-41
HBr
H
N
OH
HO
HO
NHR
C
Br
Br
C
NHR
N
S
- HMCM-41
H
Br
H
N
.
N
N
.
.
S
HBr
HBr
HBr
MCM-41
MCM-41
S
..
H2N
NHR
C
NHR
N
HO
N
S
NHR
- HBr
- H2O
S
N
H
.
N
.
HBr
HBr

1146
U. Bhoga / European Journal of Medicinal Chemistry 42 (2007) 1144e1150
Table 1
to CHS proton and phenyl protons appeared as multiplet be-
tween d 7.00 and 7.34. Further, EIMS showed a stable molec-
ular ion peak at m/z 253, confirming the structure of 9a.
Similarly, 9bei were identified. In the oxidation of 9j, forma-
tion of 10 was confirmed by its IR spectrum which showed
characteristic absorption band corresponding to S]O at
w1100 cmꢁ1 (S]O str) (Schemes 1 and 2).
Difference between the cyclocondensation of 3-(a-bromo)-acetylpyridine hy-
drobromide (7) with thioureas 8aej in presence of HMCM-41 and MeOH re-
flux alone
Compound
Yield (%) (reaction time)
in presence of HMCM-41
Yield (%) (reaction
time: 4 h) in MeOH alone
9a
9b
9c
9d
9e
9f
87 (45 min)
80 (45 min)
85 (55 min)
71 (60 min)
85 (45 min)
65 (55 min)
72 (50 min)
70 (45 min)
63 (45 min)
92 (55 min)
60
71
72
67
68
53
69
58
50
73
3. Results and discussion
9g
9h
9i
The N-aryl-4-(3-pyridyl)thiazol-2-amine analogues 9aej
and 10 were tested for their in vitro ADP-induced platelet ag-
gregation inhibitory activity on human blood platelets. All the
test compounds showed inhibitory effect on platelet aggrega-
tion in a concentration dependant manner. Among the test
compounds, N-(20-flourophenyl)-4-(3-pyridyl)thiazol-2-amine
(9e) was found to be the most potent, IC50 4.84 ꢀ 10ꢁ7 M.
The results showed that lipophilicity attributed to the de-
creased platelet aggregation inhibitory activity. However, the
mechanism of inhibition is not known.
Since the sulfoxide 10 showed IC50 1.41 ꢀ 10ꢁ6 M, the
synthesis of sulfoxides of the other analogues [34] has been
proposed to prepare and investigate for their ADP-induced
platelet aggregation inhibitory activity (Fig. 2; Table 2).
9j
Thus, HMCM-41 can be recycled without any loss of shape
selectivity. The use of HMCM-41 improved the yields of con-
densation products by 3e27%, with 45e60 min reaction time
where as the reaction time for condensation in methanol by
a standard procedure [11] was 4 h with 50e73% yields (Table
1). The formation of 9a was identified by its H NMR and
1
mass spectroscopy. In H NMR, the singlet for CH2 protons
of 3-(a-bromo)-acetylpyridine hydrobromide was disappeared
at d 5.10. Further, 9a showed a singlet at d 7.70 corresponding
1
R2
R4
R1
R5
O
R1
R5
R2
R4
S
R3
NH
S
C
HMCM-41
R3
N
+
NH
NH2
Br
MeOHreflux
40-60min
65-87 %
N
HBr
7
.
N
.
HBr
8a-g
9a-g
9a :
9b :
9c :
9d :
9e :
9f :
R1 = R2 = R3 = R4 = R5 = H;
R1 = R2 = R4 = R5 = H; R3 = CH3
R1 = R2 = R4 = R5 = H; R3 = NO2
R2 = R3 = R4 = R5 = H; R1 = C2H5
R2 = R3 = R4 = R5 = H; R1 = F
R1 = R2 = R4 = R5 = H; R3 = n-butyl
R2 = R3 = R4 = H; R1 = R5 = C2H5
9g :
S
N
H
O
S
C
N
HMCM-41
N
H
+H2N
Br
MeOHreflux
45 min
N
.
N
.
HBr
7
HBr
63%
9i
8i
S
NH2
O
S
C
N
HMCM-41
NH2
+H2N
MeOHreflux
55min
Br
N
N
.
.
HBr
HBr
92%
8j
9j
7
Scheme 1.

U. Bhoga / European Journal of Medicinal Chemistry 42 (2007) 1144e1150
1147
Table 2
The ADP-induced antiplatelet aggregation activity of the test compounds 9aej
and 6ael which were carried out under identical conditions [11]
O
S
S
NH2
NH2
m CPBA
N
N
Entry
Inhibition of platelet
aggregationa IC50 (M)
CHCl3 / 0°C
15min / 90%
N
N
.
.
1.45 ꢀ 10ꢁ6
HBr
HBr
9a
9b
9d
9e
9g
9h
9i
9j
10
2 ꢀ 10ꢁ6
1.35 ꢀ 10ꢁ6
4.84 ꢀ 10ꢁ7
2.19 ꢀ 10ꢁ6
2.1 ꢀ 10ꢁ6
Scheme 2.
3.1. Structureeactivity relationships
2.89 ꢀ 10ꢁ6
1.41 ꢀ 10ꢁ6
0.042 ꢀ 10ꢁ6
0.25 ꢀ 10ꢁ6
>10 ꢀ 10ꢁ6
0.085 ꢀ 10ꢁ6
0.065 ꢀ 10ꢁ6
1.8 ꢀ 10ꢁ6
10
6a
6b
6c
6d
6e
6f
The SAR studies of the N-aryl-4-(3-pyridyl)thiazol-2-
amine derivatives were established through the structural anal-
ysis of the compounds that differ in the functionalisation.
Among the series, N-(20-flourophenyl)-4-(3-pyridyl)thiazol-
2-amine (9e) was found to be most active. This compound is
flanked by flourine at R1. The high electronegativity of the
flourine, relatively of small size, and its ability to form hydro-
gen bond facilitating hydrophilicity might be contributing for
the enhanced activity. There are structural similarities of 9e
with most potent compound 5 which has imidazole instead
of thiazole system flanked by 2-flourophenyl ring. Compound
9a without any substitution on phenyl ring showed moderate
activity. But 9d showed better inhibition than 9a indicating
lipophilicity and steric factors on introducing one ethyl group
at R1. However, substitution of two ethyl groups at R1 and R5
in 9g did not substantially improve potency. On the other hand
amine directly attached to naphthyl system 9i, drastically de-
creased the activity.
Compound 10 showed good inhibitory activity but less than
9d. This suggests that NH2 flanked by aryl substituents are
shown to exhibit competitive activity. Introduction of methyl
group at R3 of 9b or NH2 directly linked to benzyl system
9h resulted in almost equivalent or less potent derivatives.
Examination of the biological activities of these com-
pounds indicates that the variation of the substituents on aro-
matic system in terms of position, bulkiness and
electronegativity resulted in the variation of inhibitory activity
6g
6h
6i
6 ꢀ 10ꢁ6
0.16 ꢀ 10ꢁ6
0.23 ꢀ 10ꢁ6
0.17 ꢀ 10ꢁ6
0.046 ꢀ 10ꢁ6
0.096 ꢀ 10ꢁ6
6j
6k
6l
a
In vitro inhibition of ADP-induced (2.5 mM) human platelet aggregation.
on platelet aggregation. Introduction of substituents at R1 or
R5 showed good activity compared to the substituents at R3
position. Therefore, it is theoretically assumed that 9c with
NO2 group at R3 might not be encouraging due to electron
withdrawing nature of the nitro group. Similarly n-butyl group
at R3 theoretically increases lipophilicity and steric factors
compared to methyl substituent in 9b. Results showed that
substitution at R3 did not exhibit encouraging activity profile.
Substitution of amine group with aryl or cycloalkyl ring sys-
tems exhibited moderate to good activity like in compounds
5 and 6ael. This is also proven by experimental efforts in
case of compound 10. Therefore, compound 9j might not be
an encouraging target. On the whole, the small size of flourine
at favorable position and high electronegativity in compound
9e proved to be the most potent among the analogues.
4. Experimental section
4.1. Chemistry
All chemicals were reagent grade and used as purchased.
All the solvents were purified using standard literature proce-
dures. Column chromatography was performed using ACME
1
silica gel (100e200 mesh). H NMR (200 MHz, DMSO-d6)
spectra were recorded on a Varian Gemini 200 spectrometer
and the chemical shifts were expressed in d (ppm) using
TMS (tetra methyl silane) as an internal standard. Mass spec-
tra were recorded on VG 70-70H spectrometer (SHRADER
Laboratories Inc). Progress of the reaction was monitored by
1
TLC. H NMR refers to hydrobromide salts while elemental
analysis refers to the free bases of the analogues.
Fig. 2. Percent inhibitory effect of the test compounds at four different concen-
trations on ADP-induced human platelet aggregation.

1148
U. Bhoga / European Journal of Medicinal Chemistry 42 (2007) 1144e1150
4.1.1. Typical procedure for the preparation of
hydrobromide salt of N-phenyl-4-(3-pyridyl)thiazol-2-amine
(9a)
100%), 252 (Mþ ꢁ F, 50%); mp 150 ꢂC; Anal. Calcd for
C14H10N3SF: C, 61.98; H, 3.72; N, 15.79. Found: C, 62.04;
H, 3.75; N, 15.56.
A mixture of 3-(a-bromo)-acetylpyridine hydrobromide (7)
(2.81 g, 10 mmol), phenyl thiourea 9a (1.52 g, 10 mmol) and
a catalytic amount of HMCM-41 catalyst in methanol
(15 mL) was allowed to reflux for 45e60 min. After the reac-
tion was complete (TLC), solvent was filtered giving methanol
washings (50 mL) to remove HMCM-41 catalyst. Combined
filtrate was evaporated to afford a residue which was purified
by column chromatography using ethyl acetate:pet ether
(1:9) to furnish hydrobromide salt of 2-phenylamino-4-
(3-pyridyl)thiazole (9a) as a solid. Similarly, 9bej were
prepared.
4.1.7. Hydrobromide salt of N-(40-n-butyl phenyl)-4-(3-
pyridyl)thiazol-2-amine (9f)
Yield 65%, 1H NMR (200 MHz, DMSO-d6): d 0.90 (t,
3 Hz, 3H), 1.40 (m, 2H), 1.60 (m, 2H), 2.58 (t, J ¼ 3 Hz,
2H), 6.90 (s, 1H), 7.10 (d, J ¼ 8.4 Hz, 2H), 7.30 (m, 1H),
7.50 (d, J ¼ 8.5 Hz, 2H), 8.15 (m, 1H), 8.50 (m, 1H), 9.12
(s, þ1H), 9.55 (s, 1H); MS (EI): m/z 309 (Mþ, 87%), 266
(M ꢁ 43, 100%); mp 158 ꢂC; Anal. Calcd for C18H19N3S:
C, 69.87; H, 6.19; N, 13.58. Found: C, 69.97; H, 6.20; N,
13.65.
4.1.2. Hydrobromide salt of N-phenyl-4-(3-pyridyl)thiazol-
2-amine (9a)
4.1.8. Hydrobromide salt of N-(2,6-diethyl phenyl)-4-(3-
pyridyl)thiazol-2-amine (9g)
1
Yield 87%, H NMR (200 MHz, DMSO-d6): d 7.00 (m,
Yield 72%, 1H NMR (200 MHz, DMSO-d6): d 1.20 (t,
J ¼ 3 Hz, 6H, 2 ꢀ CH3), 2.70 (q, J ¼ 5.7 Hz, 4H, 2 ꢀ CH2),
6.61 (s, 1H), 7.05 (m, 1H), 7.80 (m, 1H), 7.20 (s, 1H), 7.30
(m, 1H), 7.85(m, 1H), 8.40 (m, 1H), 8.81 (s, 1H), 9.20 (s,
1H); MS (EI): m/z 253 (Mþ, 100%); mp 153 ꢂC; Anal. Calcd
for C18H19N3S: C, 69.87; H, 6.19; N, 13.58. Found: C, 69.96;
H, 6.22; N, 13.63.
1H), 7.15e7.32 (m, 4H), 7.53 (m, 1H), 7.70 (s, 1H), 7.65
(m, 1H), 8.70 (m, 1H), 9.01 (s, 1H), 10.19 (br s, 1H); MS
(EI): m/z 253 (Mþ, 100%), 252 (Mþ e 1, 70%); mp 168 ꢂC;
Anal. Calcd for C14H11N3S: C, 66.38; H, 4.38; N, 16.59.
Found: C, 66.57; H, 4.50; N, 16.78.
4.1.3. Hydrobromide salt of N-( p-toluyl)-4-(3-pyridyl)-
thiazol-2-amine (9b)
4.1.9. Hydrobromide salt of N-benzyl-4-(3-pyridyl)thiazol-
2-amine (9h)
Yield 80%, 1H NMR (200 MHz, DMSO-d6): d 2.25 (s, 3H),
7.09 (d, J ¼ 8.4 Hz, 2H), 7.50 (d, J ¼ 8.7 Hz, 2H), 7.65 (m,
1H), 8.02 (m, 1H), 8.80 (m, 1H), 8.95 (m, 1H), 9.42 (s, 1H),
10.1 (s, 1H); MS (EI): m/z 267(Mþ, 100%), 266 (Mþ ꢁ 1,
50%); mp 155 ꢂC; Anal. Calcd for C15H13N3S: C, 67.39; H,
4.90; N, 15.72. Found: C, 67.58; H, 4.93; N, 15.80.
Yield 70%, 1H NMR (200 MHz, DMSO-d6): d 4.57 (s, 2H),
6.80 (s, 1H), 7.30 (m, 5H), 7.80 (m, 1H), 8.10 (m, 1H), 8.42
(m, 1H), 9.00 (s, 1H); MS (EI): m/z 267 (Mþ, 100%), 91(ben-
zyl, 100%); mp 192 ꢂC; Anal. Calcd for C15H13N3S: C, 67.39;
H, 4.90; N, 15.72. Found: C, 67.56; H, 4.91; N, 15.87.
4.1.4. Hydrobromide salt of N-( p-nitrophenyl)-4-(3-
pyridyl)thiazol-2-amine (9c)
4.1.10. Hydrobromide salt of N-(1-naphthyl)-4-(3-pyridyl)-
thiazol-2-amine (9i)
Yield 85%, 1H NMR (200 MHz, DMSO-d6): d 7.20 (s, 1H),
7.40 (m, 1H), 7.49 (s, 1H), 7.79 (d, 2H, J ¼ 7.2 Hz), 8.2 (d,
J ¼ 7.4 Hz, 2H), 8.58 (m, 1H), 9.20 (s, 1H), 10.60 (s, 1H);
MS (EI): m/z 298 (Mþ, 100%), 252 (Mþ ꢁ NO2, 80%); mp
187 ꢂC; Anal. Calcd for C14H10N4SO2: C, 56.37; H, 3.38; N,
18.78. Found: C, 56.40; H, 3.43; N, 18.82.
Yield 63%, 1H NMR (200 MHz, DMSO-d6): d 7.00 (s, 1H),
7.34 (m, 1H), 7.48 (m, 3H), 7.62 (m, 1H), 8.16 (m, 2H), 8.26
(m, 1H), 8.48 (brþs, 1H), 9.10 (br s,þ1H), 9.82 (br s, 1H); MS
(EI): m/z 303 (M , 100%), 304 (M þ 1, 98%); mp 187 ꢂC;
Anal. Calcd for C18H13N3S: C, 71.26; H, 4.32; N, 13.85.
Found: C, 71.38; H, 4.44; N, 13.97.
4.1.5. Hydrobromide salt of N-(20-ethyl phenyl)-4-(3-
pyridyl)thiazol-2-amine (9d)
4.1.11. Hydrobromide salt of 4-(3-pyridyl)thiazol-2-amine
(9j)
Yield 71%, 1H NMR (200 MHz, DMSO-d6): d 1.30 (t,
J ¼ 3 Hz, 3H), 2.72 (m, 2H), 6.83 (s, 1H), 7.19 (m, 1H),
7.30 (m, 3H), 7.39 (s, 1H), 7.63 (m, 1H), 8.10 (m, 1H), 8.51
(m, 1H), 9.40 (s, 1H); MS (EI): m/z 281 (Mþ, 100%), 248
(Mþ ꢁ ethyl, 50%); mp 155 ꢂC; Anal. Calcd for C16H15N3S:
C, 68.30; H, 5.37; N, 14.93. Found: C, 68.48; H, 5.40; N,
14.98.
Yield 92%, 1H NMR (200 MHz, DMSO-d6): d 7.60 (s, 1H),
8.20 (m, 1H), 8.80 (m, 1H), 8.83 (m, 1H), 9.14 (s, 14); MS
(EI): m/z 177 (Mþ, 100%), 178 (Mþ þ 1, 10%); mp 204 ꢂC;
Anal. Calcd for C8H7N3S: C, 54.22; H, 3.98; N, 23.71. Found:
C, 54.39; H, 3.98; N, 23.81.
4.1.12. Preparation of S-oxo-4-(3-pyridyl)thiazol-2-amine
(10)
4.1.6. Hydrobromide salt of N-(20-flourophenyl)-4-(3-
A solution of 9j (100 mg, 0.32 mmol) and m-chloroperben-
zoic acid (55 mg, 0.32 mmol) in chloroform (10 mL) was
stirred at 0 ꢂC for 15 min under N2 atmosphere. Reaction
was monitored by TLC. After reaction was complete (TLC),
reaction mixture was quenched with aqueous sodium bisulfate
pyridyl)thiazol-2-amine (9e)
1
Yield 85%, H NMR (200 MHz, DMSO-d6): d 7.00 (m,
4H), 7.38 (m, 1H), 8.15 (m, 1H), 8.44 (m, 1H), 8.60 (m,
1H), 9.20 (m, 1H), 9.65 (s, 1H); MS (EI): m/z 271 (Mþ,

U. Bhoga / European Journal of Medicinal Chemistry 42 (2007) 1144e1150
1149
solution to remove the traces of m-CPBA and extracted with
References
chloroform (5 ꢀ 5 mL). Combined organic layer was washed
with aqueous NaHCO3, brine and dried over anhydrous
Na2SO4. Evaporation of the solvent under reduced pressure
gave a solid which was purified by column chromatography
using silica gel (100e200 mesh), ethyl acetate and pet ether
(2:8) as eluent to afford sulfoxide 10 as a white solid (mp
232 ꢂC, 90%); 1H NMR (200 MHz, DMSO-d6): d 6.73 (s,
2H), 6.83 (s, 1H), 7.30 (m, 1H), 8.14 (m, 1H), 8.40 (m, 1H),
8.99 (s, 1H); MS (EI): m/z 177 (Mþ ꢁ O); mp 232 ꢂC; Anal.
Calcd for C8H7N3SO: C, 49.73; H, 3.65; N, 21.76. Found:
C, 49.88; H, 3.78; N, 21.79.
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