One-pot, four-component synthesis of novel imidazo[2,1-b]thiazol-5-amine derivatives

Article abstract of DOI:10.1055/s-0032-1317515

Novel imidazo[2,1-b]thiazol-5-amine derivatives were synthesized by a one-pot, four-component reaction of 2-bromoacetophenone derivatives, aromatic aldehydes, thiourea, and isocyanides in the presence of ammonium chloride (NHl) in toluene under reflux conditions. Moderate to good yields resulted and the reaction showed tolerance toward a range of aromatic aldehydes with electron-donating and electron-withdrawing substituents on either para or ortho positions. Georg Thieme Verlag KG Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317515

PAPER
▌3649
pOapnere-Pot, Four-Component Synthesis of Novel Imidazo[2,1-b]thiazol-5-amine
Derivatives
Imidazo[2,1-b]thiazol-5-amine Derivatives
Mohammad Mahdavi,a Mehdi Asadi,b Mina Saeedi,a Mostafa Ebrahimi,a Mohammad A. Rasouli,b Parviz R. Ranjbar,b
Alireza Foroumadi,a Abbas Shafiee*a
a
Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center,
Tehran University of Medical Sciences, Tehran 14176, Iran
b
School of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
Fax +98(21)66461178; E-mail: ashafiee@ams.ac.ir
Received: 31.07.2012; Accepted after revision: 10.10.2012
isocyanide13,14 are also increasingly being employed and
Abstract: Novel imidazo[2,1-b]thiazol-5-amine derivatives were
they have been particularly important tools in pharmaceu-
synthesized by a one-pot, four-component reaction of 2-bromoace-
tical chemistry.15
tophenone derivatives, aromatic aldehydes, thiourea, and isocya-
nides in the presence of ammonium chloride (NH4Cl) in toluene
under reflux conditions. Moderate to good yields resulted and the
reaction showed tolerance toward a range of aromatic aldehydes
preparation of bioactive molecules,19–21 we disclose here-
with electron-donating and electron-withdrawing substituents on
either para or ortho positions.
As a part of our studies on the development of novel syn-
thetic procedures in heterocyclic chemistry16–18 and on the
in a novel protocol for the synthesis of imidazo[2,1-b]thi-
azol-5-amine derivatives based on MCRs; this new
method can underpin other useful approaches to drug de-
sign especially in heterocyclic medicinal chemistry
(Scheme 1).
Key words: heterocyclic compounds, multicomponent reactions,
isocyanides, thiourea, ammonium chloride
Bienaymé and Bouzid introduced a three-component re-
action of heteroaromatic amidines, aldehydes, and isocy-
anide to synthesize fused 3-aminoimidazoles.22a Since
then, the synthesis of various heterocycles22b with impor-
tant biological activities22c has been reported based on
such a three-component reaction.
Among nitrogen- and sulfur-containing heteroaromatic
compounds, imidazole and imidazo[2,1-b]thiazole deriv-
atives are crucial core structures used to create drugs and
materials. They exhibit significant biological activities in-
cluding antitumor,1–3 antibacterial,4,5 antifungal,6 and an-
tihelmintic properties.7 They have also been studied as
potent enzyme inhibitors and cellular activity against
IGF-IR, EGFR, and ErbB2 has been noted.8 A series of
imidazo[2,1-b]thiazole acetohydrazones was synthesized
by Andreani et al. and their diuretic activity was screened;
these studies showed that a potent diuretic activity was
confirmed for the 2-methyl derivative bearing a phenyl
ring at the 6-position.9
In this work, we have focused on the four-component re-
action of 2-bromoacetophenones 1, aromatic aldehydes 2,
thiourea 3, and isocyanides 4 (Scheme 1), in which 4-ar-
ylthiazol-2-amine derivatives 6 are produced in situ by the
reaction of 1 and 3, followed by reaction of intermediate
6 with compounds 2 and 4 to give the title compounds 5
(Scheme 2).
Multicomponent reactions (MCRs) offer convenient, safe,
short, selective, high yielding, and often environmentally
benign procedures, based on readily available starting ma-
terials.10 In addition, the synthetic efficiency and rational
design, particularly in heterocyclic chemistry, has been
enhanced by the use of multicomponent reaction strate-
The synthesis of imidazo[2,1-b]thiazol-5-amine deriva-
tives (Scheme 1) was initially investigated by examining
the reaction of 2,4′-bromoacetophenone (1 mmol), 2-ni-
trobenzaldehyde (1 mmol), thiourea (1 mmol), and cyclo-
hexyl isocyanide (1.2 mmol). To optimize the reaction
conditions, the mentioned model reaction was carried out
in various solvents and under solvent-free conditions. The
gies.11,12
Multicomponent
reactions
based
on
R
HN
Ar1
O
S
O
NH4Cl
Br
N
+
+
+
R
Ar1
H2N
NH2
Ar2
N C
Ar2
H
toluene, reflux
12 h
S
N
1
2
3
4
5
Scheme 1 Synthesis of imidazo[2,1-b]thiazol-5-amine derivatives 5
SYNTHESIS 2012, 44, 3649–3654
Advanced online publication: 12.11.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1317515; Art ID: SS-2012-N0418-OP
© Georg Thieme Verlag Stuttgart · New York

3650
M. Mahdavi et al.
PAPER
Cl
H3N
H
Cl
H3N
O δ+
H
NH2
H2N
NH
O
N
Ar2
H
O
S
δ+
S
Ar1
S
Br
Ar1
Ar1
+
H2N
NH2
2
1
3
6
Ar2
Cl
R
Ar1
HN
δ+
N
H
NH3
N
R
N
C
4
Ar2
N
S
N
[4+1] cycloaddition
S
Ar1
5
7
Scheme 2 Plausible mechanism for the synthesis of imidazo[2,1-b]thiazol-5-amine derivatives 5
results showed that the yield of the reaction in toluene was The structure of 3-(4-bromophenyl)-N-cyclohexyl-6-(2-
higher than those obtained in other organic solvents, in nitrophenyl)imidazo[2,1-b]thiazol-5-amine (5a) was con-
water, and under solvent-free conditions. It should be not- firmed by mass spectroscopy fragmentation pattern anal-
ed that the corresponding product 5a (Table 1, entry 1) ysis, and on the basis of its 1H and 13C NMR spectra. The
was obtained upon heating to reflux and no reaction was MS peak (m/z 496/498) associated with the molecular ion
observed at room temperature. Although toluene was was observed and was in accordance with calculated mass
found to be the best solvent, the yield of the reaction was for C23H21BrN4O2S.
still only 10%. Since the usefulness of ammonium chlo-
The MS shows a peak (m/z 413/415) that is related to
elimination of the cyclohexyl ring. A fairly strong peak
was also observed (m/z 371/373) resulting from loss of
CN and NH2 from the latter ion. The observation of two
ride has been demonstrated in a number of isocyanide-
based MCRs23–25 and also in other chemical reactions,26,27
the model reaction was then conducted in the presence of
NH4Cl (1 mmol) in toluene under reflux conditions; under
peaks with similar intensity in the mentioned fragments
these conditions the corresponding product was obtained
indicates the presence of the bromine atom. Elimination
in good yield (75%).
of Br· gave the expected peak (m/z 292).
Table 1 Synthesis of Imidazo[2,1-b]thiazol-5-amine Derivatives 5
R
HN
Ar1
O
S
O
NH4Cl
Br
N
+
+
+
R
Ar1
H2N
NH2
Ar2
N C
Ar2
H
toluene, reflux
12 h
S
N
1
2
3
4
5
Entry
Ar1
Ar2
R
Product
Yield (%)a
1
4-BrC6H4
Ph
2-O2NC6H4
4-O2NC6H4
2-FC6H4
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
5a
5b
5c
5d
5e
5f
75
85
78
70
80
60
75
90
80
65
2
3
Ph
4
Ph
4-MeOC6H4
2-BrC6H4
4-ClC6H4
2-O2NC6H4
4-O2NC6H4
Ph
5
Ph
6
4-BrC6H4
Ph
7
1,1,3,3-tetramethylbutyl
1,1,3,3-tetramethylbutyl
1,1,3,3-tetramethylbutyl
1,1,3,3-tetramethylbutyl
5g
5h
5i
8
4-BrC6H4
4-MeOC6H4
4-BrC6H4
9
10
4-ClC6H4
5j
a Isolated yield.
Synthesis 2012, 44, 3649–3654
© Georg Thieme Verlag Stuttgart · New York

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Imidazo[2,1-b]thiazol-5-amine Derivatives
3651
1H NMR spectrum of 5a consisted of multiplet signals for hydes 2 and isocyanides 4 the products obtained were an-
the cyclohexyl rings (δ = 0.51–1.32 ppm, 10 H), N-CH alyzed and their physicochemical data were found to be in
resonance (δ = 1.92–1.95 ppm, 1 H), and a singlet signal good agreement with those obtained from the one-pot,
for the cyclohexyl NH group (δ = 2.34 ppm, 1 H). The four-component reactions.
proton associated with the thiazole ring gave a singlet at
To verify the structure of prepared compounds, we pre-
δ = 6.65 ppm and signals related to eight aromatic protons
pared an authentic sample of N-cyclohexyl-3-methyl-6-
were observed around 7.42–7.85 ppm. The 13C spectrum
phenylimidazo[2,1-b]thiazole-5-amine (11; Scheme 3), as
showed 18 distinct resonances, as expected.
a known compound reported by Adib et al.29 We therefore
As indicated in Table 1, the variability of the four-compo- synthesized 11 by using our procedure (Scheme 3) and,
nent reaction with respect to the isocyanides and 2-bromo- for this purpose, chloroacetone 8 was used instead of 2-
acetophenone derivatives was examined under the bromoacetophenone derivatives and its reaction with
optimized conditions. To explore the limitations of this re- benzaldehyde 9, thiourea 3, and cyclohexyl isocyanide 10
action, we extended it to various para- and ortho-substi- was conducted under the optimal conditions; the corre-
tuted benzaldehydes. As can be seen in Table 1, the yield sponding product was obtained and the structure of 11
of products seems to be affected by the nature of substitu- was confirmed.
ents and their positions on the benzaldehyde. The yields
In summary, we have developed a novel, efficient, one-
increased when electron-withdrawing para-substituents
pot, four-component synthesis of imidazo[2,1-b]thiazol-
were present, and evidently steric effects operate in the
5-amine derivatives through the reaction of 2-bromoace-
tophenone derivatives, aromatic aldehydes, thiourea, and
isocyanides in the presence of ammonium chloride. No
case of ortho-substituted benzaldehydes for which lower
yields were observed.
Additionally, the reactivity of more hindered isocyanide undesirable side reactions were observed and products
(1,1,3,3-tetramethylbutyl isocyanide) was investigated in were obtained in moderate to good yields.
the four-component reaction. In this case, we found that
the reactions proceeded quite well and no significant dif-
ference was observed.
Melting points were measured with a Kofler hot stage apparatus and
are uncorrected. H and 13C NMR spectra were recorded with a
Bruker FT-500, using TMS as an internal standard. IR spectra were
obtained with a Shimadzu 470 spectrophotometer (KBr disks). MS
were recorded with an Agilent Technology (HP) mass spectrometer
operating at an ionization potential of 70 eV. Elemental analysis
was performed with an Elementar Analysensystem GmbH VarioEL
CHNS mode.
1
It should be noted that in the absence of ammonium chlo-
ride the corresponding products were obtained in poor
yields and, in some cases, no reaction occurred. It is worth
mentioning that in the presence of NH4Cl (1 mmol), the
reactions proceed either with electron-withdrawing or
electron-donating para- and ortho-substituted benzalde-
hydes and desired products were obtained in reasonable
yields.
Synthesis of Imidazo[2,1-b]thiazol-5-amine Derivatives; Gener-
al Procedure
A mixture of 2-bromoacetophenone derivative 1 (1 mmol), appro-
priate aromatic aldehyde 2 (1 mmol), thiourea 3 (1 mmol), isocya-
nide derivative 4 (1.2 mmol), ammonium chloride (1 mmol), and
toluene (5 mL) was heated at reflux for 12 h. Upon completion of
the reaction (monitored by TLC), the mixture was cooled to r.t., the
solvent was removed under reduced pressure, and the residue was
purified by column chromatography (petroleum ether–EtOAc, 3:1).
A plausible mechanism for the formation of the imid-
azo[2,1-b]thiazol-5-amine derivatives 5 is shown in
Scheme 2. It can be assumed that the initial step is the for-
mation of 4-arylthiazol-2-amines 6 from the reaction of 2-
bromoacetophenone derivatives 1 and thiourea 3. As re-
ported previously, heteroaromatic amidines react effi-
ciently with isocyanide and aldehydes.22 Therefore,
aromatic aldehyde 2 reacts with 6, producing N-benzili-
dene-4-arylthiazol-2-amine derivatives 7. Finally [4+1]
cycloaddition of isocyanide 4 with 7 gives the products
5a–k. To support the proposed mechanism, compound 6
was isolated from the reaction mixture and its structure
was confirmed by comparison with authentic samples.28
Upon treatment of this compound with aromatic alde-
3-(4-Bromophenyl)-N-cyclohexyl-6-(2-nitrophenyl)imid-
azo[2,1-b]thiazol-5-amine (5a)
Yield: 0.37 g (75%); orange powder; mp 199–200 °C.
IR (KBr): 3351, 2927, 2851, 1611, 1569, 1444, 1361 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.51–1.32 (m, 10 H, 5 × CH2, cy-
clohexyl), 1.92–1.95 (m, 1 H, NCH), 2.34 (s, 1 H, NH), 6.65 (s, 1 H,
CH, thiazole), 7.42–7.47 (m, 3 H, H-4, H-2′, H-6′), 7.60–7.65 (m,
3 H, H-5, H-3′, H-5′), 7.80 (d, J = 7.6 Hz, 1 H, H-6), 7.84 (d, J =
8.0 Hz, 1 H, H-3).
HN
O
S
O
NH4Cl
Cl
+
+
+
N C
N
H2N
NH2
Ph
H
Ph
toluene, reflux
12 h
S
N
11
8
9
3
10
Scheme 3 Synthesis of N-cyclohexyl-3-methyl-6-phenylimidazo[2,1-b]thiazol-5-amine (11)
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3649–3654

3652
M. Mahdavi et al.
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13C NMR (125 MHz, CDCl3): δ = 24.1, 25.4, 32.3, 57.2, 110.3,
123.9, 124.2, 127.9, 128.4, 128.6, 129.1, 130.8, 131.6, 132.1, 132.2,
134.9, 146.2, 149.1.
MS: m/z (%) = 498 (35) [M + 2]+, 496 (35) [M]+, 415 (10), 371 (35),
292 (20), 119 (100), 83 (35), 55 (94).
IR (KBr): 3280, 2929, 2852, 1650, 1586 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.43–1.29 (m, 10 H, 5 × CH2, cy-
clohexyl), 1.93–1.96 (m, 1 H, NCH), 2.85 (d, J = 8.1 Hz, 1 H, NH),
6.61 (s, 1 H, CH, thiazole), 7.21 (dt, J = 7.7, 1.6 Hz, 1 H, H-4), 7.36
(dt, J = 7.7, 1.0 Hz, 1 H, H-5), 7.46–7.47 (m, 3 H, H-3′, H-4′, H-5′),
7.55 (dd, J = 7.7, 1.6 Hz, 1 H, H-6), 7.37–7.67 (m, 3 H, H-3, H-2′,
H-6′).
13C NMR (125 MHz, DMSO-d6): δ = 23.5, 25.1, 31.7, 55.9, 109.8,
123.3, 127.1, 127.9, 129.0, 129.3, 129.5, 132.4, 132.8, 133.2, 135.6,
137.2, 143.8, 146.5.
Anal. Calcd for C23H21BrN4O2S: C, 55.54; H, 4.26; N, 11.26.
Found: C, 55.74; H, 4.40; N, 11.15.
N-Cyclohexyl-6-(4-nitrophenyl)-3-phenylimidazo[2,1-b]thia-
zol-5-amine (5b)
Yield: 0.35 g (85%); powder yellow; mp 188–190 °C.
IR (KBr): 3321, 2924, 2847, 1596, 1556, 1491, 1369 cm–1.
1H NMR (500 MHz, DMSO-d6): δ = 0.67–1.34 (m, 10 H, 5 × CH2,
cyclohexyl), 1.94–1.99 (m, 1 H, NCH), 3.90 (d, J = 3.7 Hz, 1 H,
NH), 7.18 (s, 1 H, CH, thiazole), 7.53–7.54 (m, 3 H, H-3′, H-4′, H-
5′), 7.72–7.74 (m, 2 H, H-2′, H-6′), 8.21 (d, J = 9.0 Hz, 2 H, H-2, H-
6), 8.41 (d, J = 9.0 Hz, 2 H, H-3, H-5).
13C NMR (125 MHz, DMSO-d6): δ = 23.6, 25.2, 31.7, 56.3, 110.4,
123.8, 127.9, 128.0, 128.2, 129.2, 129.3, 129.4, 129.5, 131.4, 131.7,
133.2, 134.5, 145.1, 149.0.
MS: m/z (%) = 453 (30) [M + 2]+, 451 (30) [M]+, 391 (40), 370 (37),
341 (50), 308 (59), 281 (65), 263 (31), 225 (40), 189 (18), 167 (22),
149 (70), 111 (38), 91 (100), 57 (78).
Anal. Calcd for C23H22BrN3S: C, 61.06; H, 4.90; N, 9.29. Found: C,
61.22; H, 4.93; N, 9.33.
3-(4-Bromophenyl)-6-(4-chlorophenyl)-N-cyclohexylimid-
azo[2,1-b]thiazol-5-amine (5f)
Yield: 0.29 g (60%); yellow powder; mp 166–168 °C.
IR (KBr): 3386, 2925, 2850, 1597, 1489 cm–1.
MS: m/z (%) = 418 (48) [M]+, 336 (27), 308 (98), 290 (11), 189 (11),
262 (50), 159 (17), 133 (16), 102 (100), 55 (34).
1H NMR (500 MHz, CDCl3): δ = 0.66–1.47 (m, 10 H, 5 × CH2, cy-
clohexyl), 2.06–2.09 (m, 1 H, NCH), 2.56 (d, J = 4.1 Hz, 1 H, NH),
6.61 (s, 1 H, CH, thiazole), 7.35 (d, J = 8.5 Hz, 2 H, H-3, H-5), 7.46
(d, J = 8.2 Hz, 2 H, H-2′, H-6′), 7.66 (d, J = 8.2 Hz, 2 H, H-3′, H-
5′), 7.99 (d, J = 8.5 Hz, 2 H, H-2, H-6).
Anal. Calcd for C23H22N4O2S: C, 66.01; H, 5.30; N, 13.39. Found:
C, 66.25; H, 5.17; N, 13.09.
13C NMR (125 MHz, DMSO-d6): δ = 24.0, 25.3, 32.1, 56.8, 110.7,
122.6, 127.8, 128.0, 128.2, 128.7, 130.6, 131.0, 131.4, 132.2, 133.6,
137.0, 145.4.
MS: m/z (%) = 489 (5) [M + 4]+, 487 (20) [M + 2]+, 485 (15) [M]+,
404 (50), 377 (55), 296 (11), 180 (32), 159 (100), 101 (17), 83 (22),
69 (27), 55 (47).
N-Cyclohexyl-6-(2-fluorophenyl)-3-phenylimidazo[2,1-b]thia-
zol-5-amine (5c)
Yield: 0.30 g (78%); yellow powder; mp 131–132 °C.
IR (KBr): 3400, 2925, 2851, 1556, 1496 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.46–1.34 (m, 10 H, 5 × CH2, cy-
clohexyl), 1.86–1.90 (m, 1 H, NCH), 3.09 (br s, 1 H, NH), 6.60 (s,
1 H, CH, thiazole), 7.13 (ddd, J = 9.0, 8.1, 1.0 Hz, 1 H, H-3), 7.23
(dt, J = 7.5, 1.0 Hz, 1 H, H-5), 7.28–7.30 (m, 1 H, H-4), 7.46–7.48
(m, 3 H, H-3′, H-4′, H-5′), 7.65–7.67 (m, 2 H, H-2′, H-6′), 7.79 (dt,
J = 7.5, 1.7 Hz, 1 H, H-6).
13C NMR (125 MHz, DMSO-d6): δ = 23.8, 25.1, 31.9, 56.2, 110.0,
115.5, 115.7, 122.4, 122.5, 124.2, 125.5, 127.8, 128.4, 129.0, 129.3,
129.5, 130.0, 131.4, 132.2, 133.3, 144.7, 158.9 (d, JC–F = 243.0 Hz).
Anal. Calcd for C23H21BrClN3S: C, 56.74; H, 4.35; N, 8.63. Found:
C, 56.59; H, 4.21; N, 8.84.
N-(2,4,4-Trimethylpentane-2-yl)-6-(2-nitrophenyl)-3-phenyl-
imidazo[2,1-b]thiazol-5-amine (5g)
Yield: 0.34 g (75%); yellow powder; mp 169–170 °C.
IR (KBr): 3279, 2920, 2847, 1615, 1577, 1535, 1479, 1354 cm–1.
MS: m/z (%) = 391 (72) [M]+, 308 (98), 281 (100), 176 (37), 159
(20), 149 (26), 134 (40), 123 (28), 102 (80), 89 (27), 55 (45), 43
(45).
1H NMR (500 MHz, CDCl3): δ = 0.49 [s, 6 H, C(CH3)2], 0.70 [s,
9 H, C(CH3)3], 0.72 (s, 2 H, CH2), 2.47 (s, 1 H, NH), 6.63 (s, 1 H,
CH, thiazole), 7.43 (dt, J = 7.5, 1.0 Hz, 1 H, H-4), 7.50–7.54 (m,
5 H, H-2′, H-3′, H-4′, H-5′, H-6′), 7.61 (dt, J = 7.5, 1.4 Hz, 1 H, H-
5), 7.85 (dd, J = 7.5, 1.0 Hz, 1 H, H-6), 7.86 (dd, J = 7.5, 1.4 Hz,
1 H, H-3).
Anal. Calcd for C23H22FN3S: C, 70.56; H, 5.66; N, 10.73. Found: C,
70.75; H, 5.77; N, 10.61.
13C NMR (125 MHz, DMSO-d6): δ = 27.5, 30.5, 31.2, 54.9, 58.6,
110.6, 123.7, 128.1, 128.2, 129.0, 129.3, 129.7, 131.8, 131.9, 133.8,
136.4, 145.5, 149.0.
MS: m/z (%) = 448 (2) [M]+, 279 (15), 176 (13), 167 (55), 149 (100),
134 (30), 113 (17), 104 (26), 83 (35), 71 (53), 57 (96).
N-Cyclohexyl-6-(4-methoxyphenyl)-3-phenylimidazo[2,1-b]thi-
azol-5-amine (5d)
Yield: 0.28 g (70%); yellow powder; mp 168–170 °C.
IR (KBr): 3280, 2929, 2852, 1650, 1586 cm–1.
1H NMR (500 MHz, CDCl3): δ = 0.85–1.85 (m, 10 H, 5 × CH2, cy-
clohexyl), 2.01–2.06 (m, 1 H, NCH), 3.85 (s, 1 H, NH), 3.90 (s, 3 H,
OCH3), 6.97 (d, J = 8.8 Hz, 2 H, H-3, H-5), 7.19 (s, 1 H, CH, thia-
zole), 7.34–7.43 (m, 3 H, H-3′, H-4′, H-5′), 7.88 (d, J = 7.5 Hz, 2 H,
H-2′, H-6′), 8.02 (d, J = 8.8 Hz, 2 H, H-2, H-6).
13C NMR (125 MHz, DMSO-d6): δ = 24.2, 25.0, 31.9, 47.6, 55.6,
113.8, 114.4, 126.5, 127.5, 128.6, 130.7, 132.4, 133.0, 150.5, 162.9,
163.7, 165.4, 168.1.
Anal. Calcd for C25H28N4O2S: C, 66.94; H, 6.29; N, 12.49. Found:
C, 66.80; H, 5.96; N, 12.22.
3-(4-Bromophenyl)-N-(2,4,4-trimethylpentane-2-yl)-6-(4-nitro-
phenyl)imidazo[2,1-b]thiazol-5-amine (5h)
Yield: 0.47 g (90%); yellow powder; mp 185–186 °C.
IR (KBr): 3280, 2925, 2847, 1615, 1577, 1535, 1479, 1360 cm–1.
MS: m/z (%) = 403 (1) [M]+, 279 (6), 149 (70), 135 (46), 113 (12),
97 (20), 83 (65), 57 (100), 43 (66).
1H NMR (500 MHz, CDCl3): δ = 0.61 [s, 6 H, C(CH3)2], 0.84 [s,
9 H, C(CH3)3], 0.86 (s, 2 H, CH2), 2.69 (s, 1 H, NH), 6.72 (s, 1 H,
CH, thiazole), 7.45 (d, J = 8.3 Hz, 2 H, H-2′, H-6′), 7.71 (d, J =
8.3 Hz, 2 H, H-3′, H-5′), 8.20 (d, J = 9.0 Hz, 2 H, H-2, H-6), 8.26
(d, J = 9.0 Hz, 2 H, H-3, H-5).
Anal. Calcd for C24H25N3OS: C, 71.43; H, 6.24; N, 10.41. Found:
C, 71.80; H, 6.33; N, 10.66.
6-(2-Bromophenyl)-N-cyclohexyl-3-phenylimidazo[2,1-b]thia-
zol-5-amine (5e)
Yield: 0.36 g (80%); yellow powder; mp 194–195 °C.
Synthesis 2012, 44, 3649–3654
© Georg Thieme Verlag Stuttgart · New York

PAPER
Imidazo[2,1-b]thiazol-5-amine Derivatives
Acknowledgment
3653
13C NMR (125 MHz, CDCl3): δ = 28.4, 31.3, 31.6, 55.9, 61.1, 111.2,
123.5, 123.9, 127.9, 128.4, 129.0, 130.6, 132.1, 132.7, 138.2, 141.8,
146.2, 147.3.
MS: m/z (%) = 528 (5) [M + 2]+, 526 (5) [M]+, 416 (98), 397 (15),
340 (12), 180 (13), 159 (37), 57 (100).
This research was supported by grants from the research council of
Tehran University of Medical Sciences and Iran National Science
Foundation (INSF).
Anal. Calcd for C25H27BrN4O2S: C, 56.93; H, 5.16; N, 10.62.
Found: C, 57.15; H, 5.10; N, 10.80.
References
(1) Andreani, A.; Bonazzi, D.; Rambaldi, M. Farmaco Ed. Sci.
1980, 35, 896.
3-(4-Methoxyphenyl)-N-(2,4,4-trimethylpentane-2-yl)-6-phe-
nylimidazo[2,1-b]thiazol-5-amine (5i)
Yield: 0.35 g (80%); yellow powder; mp 129–131 °C.
(2) Andreani, A.; Rambaldi, M.; Andreani, F.; Bossa, R.;
Galatulas, I. Eur. J. Med. Chem. 1988, 23, 385.
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Negahbani, A. S.; Samadizadeh, M.; Firoozpour, L.;
Rajabalian, S.; Samadi, N.; Faramarzi, M. A.; Adipour, N.;
Shafiee, A.; Foroumadi, A. Eur. J. Med. Chem. 2011, 46, 65.
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268.
IR (KBr): 3245, 2925, 2865, 1660, 1575 cm–1.
1H NMR (500 MHz, DMSO-d6): δ = 0.47 [s, 6 H, C(CH3)2], 0.71 [s,
9 H, C(CH3)3], 0.80 (s, 2 H, CH2), 3.49 (s, 1 H, NH), 3.77 (s, 3 H,
OCH3), 7.11 (s, 1 H, CH, thiazole), 6.92 (d, J = 8.8 Hz, 2 H, H-3′,
H-5′), 7.49–7.54 (m, 3 H, H-3, H-4, H-5), 7.68 (d, J = 6.5 Hz, 2 H,
H-2, H-6), 7.86 (d, J = 8.8 Hz, 2 H, H-2′, H-6′).
13C NMR (125 MHz, DMSO-d6): δ = 27.8, 30.7, 31.4, 55.0, 58.8,
101.4, 109.7, 113.1, 125.5, 126.3, 127.1, 128.1, 128.4, 128.7, 128.8,
129.4, 130.1, 134.0, 140.3, 145.1, 157.9.
Anal. Calcd for C26H31N3OS: C, 72.02; H, 7.21; N, 9.69. Found: C,
72.23; H, 7.15; N, 9.55.
3-(4-Bromophenyl)-6-(4-chlorophenyl)-N-(2,4,4-trimethylpen-
tane-2-yl)imidazo[2,1-b]thiazol-5-amine (5j)
Yield: 0.19 g (0.60%); pale-yellow solid; mp 182–183 °C.
IR (KBr): 3420, 2948, 2859, 1542, 1489 cm–1.
(7) Amarouch, H.; Loiseau, P. R.; Bacha, C.; Caujolle, R.;
Payard, M.; Loiseau, P. M.; Bories, C.; Gayral, P. Eur. J.
Med. Chem. 1987, 22, 463.
(8) Fidanze, S. D.; Erickson, S. A.; Wang, G. T.; Mantei, R.;
Clark, R. F.; Sorensen, B. K.; Bamaung, N. Y.; Kovar, P.;
Johnson, E. F.; Swinger, K. K.; Stewart, K. D.; Zhang, Q.;
Tucker, L. A.; Pappano, W. N.; Wilsbacher, J. L.; Wang, J.;
Sheppard, G. S.; Bell, R. L.; Davidsen, S. K.; Hubbard, R. D.
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Eur. J. Med. Chem. 1987, 22, 19.
(10) Zhu, J.; Bienaymé, H. In Multicomponent Reactions; Wiley-
VCH: Weinheim, 2005.
1H NMR (500 MHz, CDCl3): δ = 0.58 [s, 6 H, C(CH3)2], 0.83 [s,
9 H, C(CH3)3], 0.85 (s, 2 H, CH2), 2.69 (s, 1 H, NH), 6.63 (s, 1 H,
CH, thiazole), 7.37 (d, J = 8.6 Hz, 2 H, H-3, H-5), 7.45 (d, J =
8.4 Hz, 2 H, H-2′, H-6′), 7.67 (d, J = 8.4 Hz, 2 H, H-3′, H-5′), 7.85
(d, J = 8.6 Hz, 2 H, H-2, H-6).
13C NMR (125 MHz, DMSO-d6): δ = 27.8, 30.6, 31.3, 55.1, 59.0,
111.1, 122.1, 127.2, 127.8, 129.0, 129.3, 130.8, 131.0, 131.7, 132.8,
134.3, 139.5, 145.5.
MS: m/z (%) = 517 (1.2) [M + 2]+, 515 (1) [M]+, 405 (60), 377 (25),
(11) Estévez, V.; Villacampa, M.; Menéndez, J. C. Chem. Soc.
Rev. 2010, 39, 4402.
(12) Marcaccini, S.; Torroba, T. Org. Prep. Proced. Int. 1993, 25,
141.
279 (12), 239 (10), 167 (17), 149 (100), 91 (15), 57 (48).
Anal. Calcd for C25H27BrClN3S: C, 58.09; H, 5.26; N, 8.13. Found:
C, 58.28; H, 5.33; N, 8.30.
(13) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
(14) Shaabani, A.; Maleki, A.; Rezayan, A. H.; Sarvarai, A. Mol.
Diversity 2011, 15, 41.
(15) Akritopoulou-Zanze, I. Curr. Opin. Chem. Biol. 2008, 12,
324.
Synthesis of N-Cyclohexyl-3-methyl-6-phenylimidazo[2,1-b]thi-
azol-5-amine (11)
A mixture of chloroacetone 8 (1 mmol), benzaldehyde 9 (1 mmol),
thiourea 3 (1 mmol), cyclohexylisocyanide 10 (1.2 mmol), ammo-
nium chloride (1 mmol), and toluene (5 mL) was heated at reflux for
12 h. After completion of the reaction, the mixture was cooled to
r.t., the solvent was removed under reduced pressure and the residue
was purified by column chromatography (petroleum ether–EtOAc,
7:1).
(16) Hamadi, H.; Khoobi, M.; Hossaini, Z.; Shafiee, A. Mol.
Diversity 2011, 15, 35.
(17) Hossaini, Z.; Hamadi, H.; Charati, F. R.; Khoobi, M.;
Shafiee, A. J. Heterocycl. Chem. 2011, 48, 626.
(18) Javidnia, A.; Akbarzadeh, T.; Firoozpour, L.; Khoobi, M.;
Shafiee, A.; Foroumadi, A. J. Heterocycl. Chem. 2011, 48,
454.
(19) Tahghighi, A.; Marznaki, F. R.; Kobarfard, F.; Dastmalchi,
S.; Mojarrad, J. S.; Razmi, S.; Ardestani, S. K.; Emami, S.;
Shafiee, A.; Foroumadi, A. Eur. J. Med. Chem. 2011, 46,
2602.
(20) Fallah-Tafti, A.; Foroumadi, A.; Tiwari, R.; Shirazi, A. N.;
Hangauer, D. G.; Bu, Y.; Akbarzadeh, T.; Parang, K.;
Shafiee, A. Eur. J. Med. Chem. 2011, 46, 4853.
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Saeid-Adeli, N.; Shirazi, F. H.; Shafiee, A. Eur. J. Med.
Chem. 2007, 42, 985.
N-Cyclohexyl-3-methyl-6-phenylimidazo[2,1-b]thiazol-5-amine
Yield: 0.15 g (50%); pale-yellow powder; mp 136–138 °C.
IR (KBr): 3417, 3032, 2929, 2852, 1698, 1552, 1447 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.00–1.89 (m, 10 H, 5 × CH2, cy-
clohexyl), 2.40 (s, 1 H, NH), 2.46 (s, 3 H, CH3), 3.73–3.75 (m, 1 H,
NCH), 5.60 (s, 1 H, CH, thiazole), 7.33–7.37 (m, 3 H, H-3, H-4, H-
5), 7.49 (d, J = 6.7 Hz, 2 H, H-2, H-6).
13C NMR (125 MHz, CDCl3): δ = 14.5, 23.6, 23.8, 25.8, 33.6, 34.0,
56.8, 99.4, 125.8, 128.1, 128.5, 128.9, 129.1, 132.3, 136.6, 152.0.
MS: m/z (%) = 311 (3) [M]+, 218 (22), 201 (77), 140 (21), 105 (100),
77 (42), 55 (11).
(22) (a) Bienaymé, H.; Bouzid, K. Angew. Chem. Int. Ed. 1998,
37, 2234. (b) Sharma, A.; Li, H. Synlett 2011, 1407.
Anal. Calcd for C18H21N3S: C, 69.42; H, 6.80; N, 13.49. Found: C,
69.13; H, 7.15; N, 13.25.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3649–3654

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M. Mahdavi et al.
PAPER
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Synthesis 2012, 44, 3649–3654
© Georg Thieme Verlag Stuttgart · New York