Effect of substituents on the regioselectivity of the reaction of α-tosyloxyketones with thioureas in acidic medium: Access to 2-aminothiazoles and 2-imino-2,3-dihydrothiazoles

Article abstract of DOI:10.1002/jhet.1676

Regioselective condensation of α-tosyloxyacetophenones 1 and N-substituted thioureas 2 in acidic medium to give regioisomers 2-aminothiazoles I and 2-imino-2,3-dihydrothiazoles II is largely influenced by the substituents present on 1 and 2. A mechanism,

Full text of DOI:10.1002/jhet.1676

598
Effect of Substituents on the Regioselectivity of the Reaction of
a-Tosyloxyketones with Thioureas in Acidic Medium: Access to
2-Aminothiazoles and 2-Imino-2,3-dihydrothiazoles
Vol 51
a
a
b
b
*
Ranjana Aggarwal, Rajiv Kumar, Dionisia Sanz, and Rosa M. Claramunt
aDepartment of Chemistry, Kurukshetra University, Kurukshetra 136 119, Haryana, India
bDepartamento de Quimica Organica y Bio-organica, UNED, Madrid, Spain
*
E-mail: ranjana67in@yahoo.com
Received December 15, 2011
DOI 10.1002/jhet.1676
Published online 26 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
Regioselective condensation of a-tosyloxyacetophenones 1 and N-substituted thioureas 2 in acidic medium
to give regioisomers 2-aminothiazoles I and 2-imino-2,3-dihydrothiazoles II is largely influenced by the
substituents present on 1 and 2. A mechanism, supported by DFT calculations has been proposed to explain the
observed regioselectively.
J. Heterocyclic Chem., 51, 598 (2014).
INTRODUCTION
2-imino-3-methyl-2,3-dihydrothiazole from N-methylthiourea
and a-tosyloxyacetophenones (a-TK) under acidic condi-
tions [18]. The optimum condition of concentration of HCl
and temperature to obtain 2-imino-2,3-dihydrothiazoles in
maximum ratio was established as 10M HCl:EtOH (3:5) at
80ꢀC for 45min (Scheme 1, for R═Me).
This mild and efficient method for the synthesis of
2-imino-2,3-dihydrothiazoles seems to be quite general as
several substituted aryl and thienyl groups could be incorpo-
rated at 4-position, and the desired isomers were achieved in
71–88% yield (2-aminothiazoles were present in 12–29% as
calculated from 1H NMR spectra of the crude reaction
mixtures) [18]. However, with a-tosyloxy-p-nitroacetophenone,
a complete reversal of regioselectivity was observed as the
corresponding 2-aminothiazole 4 was obtained in 96% yield,
and the desired isomer could not be isolated from the reaction
mixture (only 4%).
This observation promoted us to think that the electronic effect
of the substituent in 1, that is, electron-withdrawing NO2 group
present on the phenyl ring of a-TK, is playing a significant role
in controlling the regiochemical outcome of the reaction.
Therefore, it was decided, in the present study, to investigate a
set of reactions between various thioureas and differently
substituted a-TK to establish the role of electronic factors of
the substituents on the ratio of the two regioisomers and to
provide an insight into the mechanistic path of the reaction.
Pharmacologically, 2-aminothiazoles I are among the
most important classes of organic compounds (Fig. 1). These
compounds possess versatile biological activities; some of
these, for instance, Fentiazac [1] and Meloxicam [2], are
associated with anti-inflammatory activities. Compounds
such as Nizatidine possess anti-ulcer activity [3]. Also,
their regioisomers, that is, 2-imino-2,3-dihydrothiazoles
(2-iminothiazolines) II [4–7] (Fig. 1), although less common
as compared with 2-aminothiazoles I [8–12], possess an
additional point of structural diversity in a thiazoline-based
pharmacophore and are known to have anti-inflammatory,
analgesic, anticancer activity [13], and used as neuropro-
tective agents [14]. The most common reported routes to
2-imino-2,3-dihydrothiazole derivatives II involve the reac-
tion of bisbenzyl as well as bismethyl formamidine disulphide
dihydrobromide with ketones [15], reaction of a-thiocyanato-
ketones with anilines [4], reaction of a-haloketones with ani-
lines followed by potassium thiocyanate [6], and reaction of
N-aryl-a-oxo-a-arylethanehydrazonoyl bromides with mono-
substituted thioureas [16]. However, these methods involve
multistep synthesis, prolonged reaction time, and use of
lachrymatory substrates, and finally, yields of the products
are moderate at the best.
The use of 2-imino-2,3-dihydrothiazoles II as precursors to
synthesize a wide variety of compounds also makes them com-
pounds of interest [4,17], so an efficient and simple method is
needed to synthesize 2-imino-2,3-dihydrothiazoles by
which we can vary substituents present at various positions.
Recently, we have reported an efficient modification to the
Hantzsch thiazole reaction for the regioselective synthesis of
RESULTS AND DISSCUSSION
In the present investigation, differently substituted a-TK
1a–i and thioureas 2a–d were made to react under the
© 2013 HeteroCorporation

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Effect of Substituents: 2-Aminothiazoles and 2-Imino-2,3-dihydrothiazoles
599
The proton signal of N–CH3 of the two isomers (3 and 4
aa–ia) also provides a tool to distinguish between them and
exhibited the difference of around d 0.2 units. This difference
is due to the fact that in case of 3, the methyl attached to the
ring nitrogen experiences more deshielding than the methy-
lamino [18]. In IR spectra, N–H stretch of these two isomers
3 and 4 is at about 3050 and 3560cmꢁ1, respectively. The
known products were identified by comparison of their
melting points with those reported in literature. The structure
of all unreported compounds was confirmed on the basis of
their IR, 1H NMR spectra, and elemental analysis.
A careful analysis of the results of our study (Table 1)
indicates that the ratio of 2-imino-2,3-dihydrothiazole 3aa
was the maximum (88%) when methylthiourea 2a was
condensed with a-tosyloxy-p-methoxyacetophenone (Entry 1,
Table 1). However, it was found that by changing the posi-
tion of OCH3 from para to ortho, the ratio of 2-imino-2,3-
dihydrothiazole 3 in the reaction mixture decreased from
88 to 77% (Entry 7, Table 1), and with m-OCH3, its ratio
further decreased to 66% (Entry 8, Table 1). The drop in
the ratio of 3 may be accounted because of the steric factor
in the case of ortho and the loss of mesomeric effect in case
of meta orientation.
Figure 1. General structure of 2-aminothiazoles (I) and 2-imino-2,3-
dihydrothiazoles (II).
aforementioned optimum conditions of temperature and
concentration, that is, 10M HCl–EtOH (3:5) at 80ꢀC for
45 min (Scheme 2). The ratio of 2-imino-2,3-dihydrothiazoles
3 and 2-aminothiazoles 4 was determined on the basis of an
1
analysis of H NMR spectra of the crude reaction mixture
and is summarized in Table 1.
1
The H NMR spectra proved to be an important tool in
distinguishing the structure of the isomers 3 and 4 on the
basis of the sharp singlet because of the 5-H of the thiazole
ring. The difference in the chemical shift of the proton at
5-position of the two isomers is about d 0.9 units. In case
of 3, 5-H proton resonated upfield at d 5.65–5.99,
whereas in 4, it resonated at d 6.58–6.98. This shielding
in 3 can be attributed to the nonaromatic character of
the 2,3-dihydrothiazole ring.
Scheme 1
Scheme 2
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R. Aggarwal, R. Kumar, D. Sanz, and R. M. Claramunt
Vol 51
Table 1
Physical data, 1H NMR of 3 and 4, and ratio of 3 in reaction mixture in 10M HCl–EtOH (3:5) at 80ꢀC.
Ratio (%) of 3 in
Yields
(%)
Entry Compound
R1
R
mixturea using
d (5-H)
mp (ꢀC)
a-TK
88
85
80
71
4
79
77
66
30
23
12
7
a-BK
83
79
69
64
6
—
—
—
—
24
14
10
7
0
—
0
70
38
0
3
4
3
4
9
3
4
1
2
3
4
5
6
7
8
aa
ba
ca
da
ea
fa
ga
ha
ia
ab
bb
cb
db
eb
hb
ib
p-CH3OC6H4
p-CH3C6H4
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
5.65 6.58
5.70 6.66
5.89 6.63
5.85 6.64
5.92 6.95
5.76 6.57
5.93 6.40
5.95 6.70
5.90 6.88
5.82 6.67
5.86 6.69
5.99 6.81
5.89 6.73
79
78
73
67
—
76
65
59
24
19
10
6
76–78 [21] 120–122 [20]
72–74 [18] 126–128 [22]
78–80 [7]
70–71 [7]
Cannot
76–78 [18] 120–122 [18]
84–86
92–94
12
13
14
88
10
13
25
56
68
78
81
84
87
65
86
18
67
79
81
74
77
132–134 [7]
136–138 [7]
184–186 [7]
p-FC6H4
p-NO2C6H4
2-Thienyl
o-CH3OC6H4
112–114
144–146 [23]
145–156 [20]
m-CH3OC6H4 CH3
9
m-NO2C6H4
p-CH3OC6H4
p-CH3C6H4
C6H5
p-FC6H4
p-NO2C6H4
CH3
100–102
10
11
12
13
14
15
16
17
18
19
20
21
22
C6H5
C6H5
C6H5
C6H5
C6H5
122–124 [4] 136–138 [20]
100–102 [4] 134–136 [22]
108–110 [7] 130–132 [7]
134–136 [7] 114–116 [7]
—
114–116
—
4
0
4
0
—
6.97
5.94 6.82
6.98
196–198 [7]
145–147
120–122 [20]
156–160
m-CH3OC6H4 C6H5
18
0
69
28
0
0
0
0
15
0
59
16
0
0
0
0
m-NO2C6H4
p-CH3OC6H4
C6H5
p-NO2C6H4
p-CH3OC6H4
C6H5
C6H5
—
ac
cc
ec
ad
cd
ed
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
p-NO2C6H4
p-NO2C6H4
p-NO2C6H4
5.95 6.60
5.87 6.67
—
—
—
—
144–146
112–114 [4] 162–164 [24]
6.96
6.73
6.62
6.95
—
—
—
—
174–176
184–186 [25]
196–198
0
0
0
p-NO2C6H4
306–308 [22]
1
aRatio calculated from the H NMR spectra of the crude reaction mixture.
The reaction of a-tosyloxy-p-nitroacetophenone 1e with
N-methylthiourea 2a (Entry 5, Table 1) gave altogether
different result, and 2-imino-2,3-dihydrothiazole 3ea was
found to be the minor product (only 4%). However, by
placing NO2 group to m-position, the electron-withdrawing
mesomeric effect of NO2 group diminished, and the ratio
of 2-imino-2,3-dihydrothiazole 3ia in the reaction mixture
increased from 4 to 30% (Entry 9, Table 1). These results
clearly show that electronic factors on a-TK are governing
the course of the reaction.
To see the effect of substituents present on thiourea,
the reaction was further investigated by taking several
substituted phenylthioureas. With N-phenylthiourea 2b,
there is a change in regioselectivity, and 2-aminothiazole
4 becomes the dominant product. For instance, in the
reaction of a-tosyloxy-p-methoxyacetophenone 1a and
N-phenylthiourea 2b under the optimum reaction condi-
tions, the proportion of 2-imino-2,3-dihydrothiazole 3ab
in the reaction mixture is only 23% (Entry 10, Table 1),
whereas it was 88% by using N-methylthiourea 2a
(Entry 1, Table 1). Effect of substituents on the product
composition was again observed when 2b was made to
react with 1b–e, h–i (Entries 11–16, Table 1) under the
same reaction conditions. For instance, with m-OCH3
group on the aryl ring of a-TK 1h, the ratio of 2-imino-
2,3-dihydrothiazole 3hb decreases to 18% (Entry 15,
Table 1), whereas replacing it with p-NO2 group, 2-imino-
2,3-dihydrothiazole 3 did not form at all (Entry 14, Table 1).
These results show that the regiochemistry of the reaction
depends not only on the nature and position of substituents
present on the aryl group of a-TK but also on the nature of
the substituent present on thiourea.
Afterwards, the reaction was also explored with N-(p-
methoxyphenyl)thiourea 2c (Entries 17–19, Table 1) and
N-(p-nitrophenyl)thiourea 2d (Entries 20–22, Table 1)
with various a-TK. The reaction afforded 2-imino-2,3-
dihydrothiazole 3 in greater ratio (69%) when 2c was
made to react with 1a as compared with that obtained in
the corresponding reaction of 1a with 2b (23%). The
presence of NO2 group on phenylthiourea 2d again
shifted the regioselectivity in favor of 2-aminothiazole,
and 3 was not detected. This shows that electron-releasing/
withdrawing groups on the phenyl ring of the thiourea also
play a significant role in regiochemistry of the reaction and
result in an increase in the ratio of 3 in case of electron-
releasing groups and in favor of 4 when electron-withdrawing
groups are present.
Because this reaction is a modification of Hantzsch
thiazole synthesis, a study was undertaken to draw a
comparison between a-TK and a-bromoacetophenones
(a-BK). Some of these reactions were then performed
using a-BK in place of a-TK under identical reaction con-
ditions. It was found that although the reaction with a-BK
proceeds faster (30 min) as compared with that with a-TK
(45 min), the results summarized in Table 1 show that
the reaction with a-TK is slightly more regioselective as
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Effect of Substituents: 2-Aminothiazoles and 2-Imino-2,3-dihydrothiazoles
601
compared with the former. This may be attributed to the
slow reactivity of a-tosyloxy group as compared with that
of a-bromo, thus, making the reaction more selective.
A plausible mechanism of the reaction is given in
Scheme 3. It was assumed that in acidic medium, the
thioureas get protonated to give two forms, A and B, exist-
ing in equilibrium. DFT calculations at the hybrid B3LYP/
6-31G** level of the relative energies of the protonated
thioureas A and B (Table 2) show that for 2a (Me), 2b
(C6H5), and 2c (p-CH3OC6H4), the A form is stabilized
with respect to B, but for 2d (p-NO2C6H4), B becomes
slightly favored, so affording an explanation for the exper-
imental results.
attack of the NH2 group on the carbonyl in the second step
that would afford the cyclic intermediate C. Subsequent
dehydration of this tertiary alcohol leads to the formation of
the thiazole nucleus 4.
However, in case of 2-imino-2,3-dihydrothiazoles 3,
protonated thioureas A are involved; firstly, the carbon
of the tosyloxymethyl group is attacked by the sulfur of
thioureas involving the NH2 nitrogen. Then, in the
second step, NHR nitrogen of the open chain intermedi-
ate attacks on the carbonyl group to give the cyclic
4-hydroxythiazolidine intermediate D, which on further
loss of water and proton give 2-imino-2,3-dihydrothiazoles
3 (Scheme 3). This mechanism seems reasonable because
the thiazolidene-2-imine derivative has been prepared
by the condensation of acyl and arylacyl thioureas with
a-haloketones [19].
2-Aminothiazoles 4 were thought to be forming through
the protonated thioureas B, by involving substituted nitrogen
(NHR) in the first attack of sulfur followed by intramolecular
Scheme 3
Table 2
Absolute energies (hartrees) and relative energies (kJ/mol) of structures 2aH+–2dH+.
Protonated thioureas
2aH+ (R═CH3)
A
B
ꢁ587.87367 (0.0)
29.841
27.518
19.216
18.763
28.846
+ZPE
+ZPE
+ZPE
+ZPE
ꢁ587.84899 (0.0)
ꢁ779.62228 (0.0)
ꢁ779.58509 (0.0)
ꢁ894.15313 (0.0)
ꢁ894.10816 (0.0)
2.435
2bH+ (R═ C6H5)
2cH+ (R═p-CH3OC6H4)
2dH+ (R═p-NO2C6H4)
28.442
ꢁ984.10385 (0.0)
2.304
ꢁ984.06615 (0.0)
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R. Aggarwal, R. Kumar, D. Sanz, and R. M. Claramunt
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General procedure for the reaction between a-
tosyloxyacetophenones 1a–i (X═OTs) and N-substituted thioureas
2a–d. To the solution of N-substituted thiourea 2 (2mmol) in
10M HCl(6mL)–EtOH (10 mL) was added a-TK 1 (X═OTs)
Accordingly, it was thought that 2a and 2c are reacting
mainly through protonated form A, whereas 2d through
form B and 2b is the borderline mechanism. Furthermore,
on changing the methyl group by a phenyl group, the equi-
librium shifts towards protonated thioureas B because of
the increase in steric hindrance between substituents R
and R1 in dication D as compared with dication C; as a
result, the equilibrium shifts in favor of 2-aminothiazoles
4, and the ratio of 2-aminothiazoles increases.
Finally, as the ratio of 3 increases with electron-donating
groups and lowers with electron-withdrawing groups on R1,
it was thought that electron-withdrawing group present on
R1 facilitates the nucleophilic attack on the carbonyl group
to give D, but instability of the resulting dication E again shifts
the equilibrium towards 4. In a similar manner, electron-
donating groups present on R also favor the formation of 4
as compared with electron-withdrawing group that favors 3.
(2mmol). Resulting solution was stirred for 45min at
a
temperature of 80ꢀC. On cooling slowly, a solid separated out and
was neutralized using aq. NaOH and extracted with ethyl acetate
(3ꢂ 20mL). The combined organic extracts were dried over
anhydrous sodium sulfate, filtered,\ and concentrated. The TLC
and the 1H NMR spectra of the reaction mixture showed the
formation of two products 3 and 4 in the ratio given in
Table 1. The mixture thus obtained was separated by column
chromatography using silica gel (100–200 mesh) with petroleum
ether:ethyl acetate (99:3) afforded 3, and further elution of column
with petroleum ether:ethyl acetate (98:5) afforded 4.
2-Imino-3-methyl-4-(o-methoxyphenyl)-2,3-dihydrothiazole
(3ga). IR (cmꢁ1): 3050 (N–H). 1H NMR (CDCl3) d: 3.24 (s, 3H,
N–CH3), 3.85 (s, 3H, OCH3), 5.93 (s, 1H, 5-H), 6.97–7.05 (m, 2H,
30, 50-H), 7.24 (d, 1H, J = 9.6 Hz, 60-H), 7.47 (t, 1H, J = 7.5 Hz,
40-H). Anal. Calcd for C11H12N2OS: N 12.72, found: N 12.54.
2-Imino-3-methyl-4-(m-methoxyphenyl)-2,3-dihydrothiazole
1
(3ha). IR (cmꢁ1): 3051 (N–H). H NMR (CDCl3) d: 3.28 (s,
CONCLUSIONS
3H, N–CH3), 3.84 (s, 3H, OCH3), 5.83 (s, 1H, 5-H), 6.86–6.87
(m, 1H, 20-H), 6.91–6.99 (m, 2H, 50, 60-H), 7.35–7.37 (m, 1H,
40-H). Anal. Calcd for C11H12N2OS: N 12.72, found: N 12.62.
From our work, we have established that the reaction of
a-TK 1a–i with differently substituted thioureas 2a–d affords
2-iminothiazolines and/or aminothiazoles depending on the
nature of the substituents. A plausible mechanism, supported
by DFT/B3LYP/6-31G** calculations, is proposed.
2-Imino-3-methyl-4-(m-nitrophenyl)-2,3-dihydrothiazole(3ia).
IR (cmꢁ1): 3045 (N–H). 1H NMR (CDCl3) d: 3.43 (s, 3H, N–CH3), 5.90
0
(s, 1H, 5-H), 7.64-7.70 (m, 1H, 50-H), 8.12–8.15 (m, 2H, 40, 6 -H), 8.80–
8.83 (m, 1H, 20-H). Anal. Calcd for C10H9N3O2S: N 17.86, found: N 17.92.
In a more detailed manner, we can conclude that (i) with
a-TK having strong electron-donating substituents on para
position of the phenyl group, the ratio of 2-iminothiazolines
was the maximum with all thioureas. When such group was
located in ortho and meta, the ratio of 2-iminothiazolines
decreases; (ii) with a-TK having strong electron-withdrawing
groups on para position, the ratio of 2-iminothiazolines was
either zero or negligible with all thioureas. Changing the
position of the electron-withdrawing group to meta increases
the proportion of 2-iminothiazolines; (iii) the ratio of
2-iminothiazolines was maximum with N-methylthiourea
comparatively with arylthioureas; (iv) arylthioureas substi-
tuted in para position of phenyl ring by electron-donating
groups increased the amount of 2-iminothiazolines, and with
strong electron-withdrawing groups in the same position,
2-iminothiazolines did not form at all.
2-Imino-3-phenyl-4-(m-methoxyphenyl)-2,3-dihydrothiazole
(3hb). IR (cmꢁ1): 3052 (N–H). 1H NMR (CDCl3) d: 3.81 (s, 3H,
OCH3), 5.95 (s, 1H, 5-H), 6.73–6.76 (m, 1H, 20-H), 6.96–6.99 (m,
1H, 400-H ), 7.10–7.13 (m, 1H, 40-H), 7.15–7.21 (m, 2H, 300, 500-H),
7.33–7.36 (m, 1H, 60-H), 7.43–7.50 (m, 1H, 50-H), 7.52–7.55 (m,
2H, 200, 600-H). Anal. Calcd for C16H14N2OS: N 9.92, found: N 9.84.
2-Imino-3,4-bis-(p-methoxyphenyl)-2,3-dihydrothiazole (3ac).
IR (cmꢁ1): 3062 (N–H). 1H NMR (CDCl3) d: 3.75 (s, 3H, OCH3),
3.79 (s, 3H, OCH3), 5.95 (s, 1H, 5-H), 6.72 (d, 2H, J=8.7Hz, 300,
500-H), 6.83 (d, 2H, J=8.7Hz, 30, 50-H), 7.07 (d, 2H, J=8.7Hz, 200,
600-H), 7.95 (d, J= 8.7 Hz, 2H, 20, 60-H). Anal. Calcd for
C17H16N2O2S: N 8.97, found: N 8.75.
2-(N-Methylamino)-4-(o-methoxyphenyl)thiazole (4ga).
IR
(cm1): 3556 (N–H) 1H NMR (CDCl3) d: 3.00 (s, 3H, N–CH3),
3.92 (s, 3H, OCH3), 6.40 (s, 1H, 5-H), 6.95–7.03 (m, 2H, 30, 50-H),
7.26–7.28 (m, 1H, 60-H), 7.44–7.47 (m, 1H, 40-H). Anal. Calcd for
C11H12N2OS: N 12.72, found: N 12.65.
2-(N-Methylamino)-4-(m-methoxyphenyl)thiazole (4ha). IR
(cmꢁ1): 3550 (N–H). 1H NMR (CDCl3) d: 3.00 (s, 3H, N–
CH3), 3.86 (s, 3H, OCH3), 6.71 (s, 1H, 5-H), 6.88–6.90 (m, 1H,
20-H), 6.92–7.00 (m, 2H, 50, 60-H), 7.36–7.42 (m, 1H, 40-H).
Anal. Calcd for C11H12N2OS: N 12.72, found: N 12.57.
EXPERIMENTAL
General.
Melting points were determined in open
capillaries in electrical apparatus and are uncorrected. IR spectra
were recorded on a ABB HORIZON MB3000 (Quebec, Canada)
instrument. H NMR spectra were run on a Brucker instrument
at 300 MHz using TMS as an internal standard. a-TK were
synthesized according to literature procedure [26].
DFT calculations. The optimization of the structures of all
compounds discussed in this paper was carried out at the hybrid
B3LYP/6-31G** level [27–31] with basis sets of Gaussian type
functions using Spartan ’02 for Windows [32].
2-(N-Methylamino)-4-(m-nitrophenyl)thiazole (4ia).
IR
(cmꢁ1): 3558 (N–H). 1H NMR (CDCl3) d: 3.05 (s, 3H, N–
CH3), 6.88 (s, 1H, 5-H), 7.52–7.57 (m, 1H, 50-H), 8.26–8.32
(m, 2H, 40, 60-H), 8.66–8.69 (m, 1H, 20-H). Anal. Calcd for
C10H9N3O2S: N 17.86, found: N 17.75.
1
2-(N-Phenylamino)-4-(m-methoxyphenyl)thiazole (4hb). IR
1
(cmꢁ1): 3564 (N–H). H NMR (CDCl3) d: 3.86 (s, 3H, OCH3),
6.82 (s, 1H, 5-H), 6.85–6.88 (m, 1H, 400-H), 7.05–7.09 (m, 2H, 300,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2014
Effect of Substituents: 2-Aminothiazoles and 2-Imino-2,3-dihydrothiazoles
603
500-H), 7.29–7.31 (m, 1H, 40-H), 7.32–7.41 (m, 3H, 20, 50, 60-H),
7.42–7.49 (m, 2H, 200, 600-H). Anal. Calcd for C16H14N2OS:
N 9.92, found: N 9.87.
[3] Knadler, M. P.; Bergstrom, R. F.; Callaghan, J. T.; Rubin, A.
Drug Metab Dispos 1986, 14, 175.
[4] Sondhi, S. M.; Mahajan, M. P.; Ralhan, N. K. Indian J Chem.
1979, 17B, 632.
[5] Guirado, A.; Andreu, R.; Gálvez, J. Tetrahedron Lett, 2003,
44, 3809.
2-(N-p-Methoxyphenylamino)-4-(p-methoxyphenyl)thiazole
1
(4ac). IR (cmꢁ1): 3570 (N–H). H NMR (CDCl3) d: 3.83 (s,
[6] Kimpe, N. D.; Cock, W. D.; Keppens, M.; Smaele, D. D.;
Meszaros, A. J Heterocycl Chem 1996, 33, 1179.
[7] Bramley, S. E.; Dupplin, V.; Goberdhan, D. G. C.; Meakins,
G. D. J Chem Soc Perkin Trans 1 1987, 639.
[8] Schulman, S. J Org Chem 1949, 14, 382.
[9] Djerassi, C.; Scholz, C. R. J Org Chem 1950, 15, 694.
[10] Parkash, O.; Saini, S.; Saini, N.; Parkash, I.; Singh, S. P. Indian
J Chem 1995, 34B, 660.
[11] Ochiai, M.; Nishi, Y.; Hashimoto, S.; Tsuchimoto, Y.; Chen,
D. J Org Chem 2003, 68, 7887.
[12] Metzger, J. V. Thiazole and its Derivatives, Part 1, Ch II;
Wiley: New York, 1979.
3H, OCH3), 3.85 (s, 3H, OCH3), 6.62 (s, 1H, 5-H), 6.87–6.94
(m, 4H, 30, 50, 300, 500-H), 7.32 (d, 2H, J = 8.7 Hz, 200, 600-H),
7.76 (d, 2H, J = 9 Hz, 20, 60-H). Anal. Calcd for C17H16N2O2S:
N 8.97, found: N 8.75.
2-(N-p-Methoxyphenylamino)-4-(p-nitrophenyl)thiazole (4ec).
1
IR (nmax, cmꢁ1): 3566 (N–H). H NMR (300 MHz, CDCl3), d:
3.81 (s, 3H, OCH3), 6.96 (s, 1H, 5-H), 6.93 (d, J = 8.7 Hz, 2H,
300, 500-H), 7.34 (d, 2H, J = 8.7 Hz, 200, 600-H), 7.95 (d, 2H,
J = 9 Hz, 20, 60-H), 8.22 (d, 2H, J = 9 Hz, 30, 50-H). Anal. Calcd
for C16H13N3O3S: N 12.84, found: N 12.59.
[13] Sondhi, S. M.; Johar, M.; Singh, N. Indian J Chem 2004, 43B,
162.
[14] Cheethan, S. C.; Kerrigen, F.; Jones, C. G. P. China Patent
98804891, 2000.
[15] Bhattacharya, A. K. J Indian Chem Soc 1967, 44, 57.
[16] Joshi, K. C.; Pathak, V. N.; Sharma, S. J Heterocycl Chem
1986, 23, 775.
[17] Sondhi, S. M.; Bhattacharjee, G.; Jameel, R. K.; Shukla, R.;
Raghubir, R.; Lozach, O.; Meijer, L. Central Eur J Chem 2004, 2, 1.
[18] Aggarwal, R.; Kumar, R. Synthetic Comm 2008, 38, 2096.
[19] D’hooghe, M.; De Kimpe, N. Tetrahedron 2006, 62, 513.
[20] Potewar, T. M.; Ingale, S. A.; Srinivasan K. V. Tetrahedron
2008, 64, 5019.
[21] Hampel, W.; Mueller, I. J fuer Praktische Chemie 1968, 38,
320 (Chem. Abstr., 1969, 70, 37690w).
[22] Kabalka, G. W.; Mereddy, A. R. Tetrahedron Lett. 2006, 47,
5171.
[23] Ball, C. P.; Barrett, A. G. M.; Commerçon, A.; Compère, D.;
Kuhn, C.; Roberts, R. S.; Smith, M. L.; Venier O. Chem Commun
1998, 2019.
2-(N-p-Nitrophenylamino)-4-phenylthiazole (4cd). IR (nmax
,
1
cmꢁ1): 3560 (N–H). H NMR (300 MHz, CDCl3), d: 6.62 (d, 2H,
J0=9.0Hz, 200, 600-H), 6.96 (s, 1H, 5-H), 7.39–7.43 (m, 3H, 30, 40,
5 -H), 7.63–7.74 (m, 2H, 20, 60-H), 8.04 (d, 2H, J=9.0Hz, 300,
500-H). Anal. Calcd for C15H11N3O2S: N 14.13, found: N 14.06.
General procedure for the reaction between a-bromoacetophenones
1a–i (X═Br) and N-substituted thioureas 2a–d. To the solution of
N-substituted thiourea 2 (2 mmol) in 10M HCl (6 mL)–EtOH (10 mL)
was added a-BK 1 (X = Br) (2mmol). Resulting solution was
stirred for 30min at a temperature of 80ꢀC. On cooling slowly, a
solid separated out and was neutralized using aq. NaOH and
extracted with ethyl acetate (3ꢂ 20mL). The combined organic
extracts were dried over anhydrous sodium sulfate, filtered, and
1
concentrated. The TLC and the H NMR spectra of the reaction
mixture showed the formation of two products 3 and 4 in the ratio
given in Table 1.
Acknowledgments. We thank the Council of Scientific and
Industrial Research, New Delhi of India and MICINN of Spain
(Grant CTQ2010-16122) for financial assistance. Thanks are also
due to RSIC, CDRI, Lucknow, India for providing elemental
analysis. We also thank Prof. S. P. Singh for helpful suggestions.
[24] Dey, P. D.; Sharma, A. K.; Jayakumar, S.; Mahajan, M. P.
Indian J Chem 2002, 41B, 1286.
[25] Singh, S. P.; Sehgal S.; Sharma, P.K. Indian J Chem 1990,
29B, 533.
[26] Koser, G.F.; Relenyi, A.G.; Kalos, A.N.; Rebrovic, L.;
Wattach, R.H. J Org Chem 1982, 47, 2487.
[27] Becke, A. D. Phys Rev A 1988, 38, 3098.
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[30] Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem Phys Lett
1989, 157, 200.
REFERENCES AND NOTES
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of Drug Synthesis; Wiley: New York, 1990, 4, pp 95.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet