Efficient synthesis of imidazo[2,1-b][1,3]benzothiazoles and 9H-imidazo-[1,2-a][1,3]benzimidazoles under solvent-free conditions

Article abstract of DOI:10.1055/s-0028-1083623

An efficient synthesis of imidazo[2,1-b][1,3]benzothiazoles and 9H-imidazo[1,2-a][1,3]benzimidazoles is described from a novel multicomponent reaction between 2-aminobenzothiazoles or 2-aminobenzimidazole, benzaldehydes, and imidazoline-2,4,5-tri-one under solvent-free conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083623

LETTER
2941
Efficient Synthesis of Imidazo[2,1-b][1,3]benzothiazoles and 9H-Imidazo-
[1,2-a][1,3]benzimidazoles under Solvent-Free Conditions
S
ynthesisof Imidazo[2
e
,1-
b
][1,3]b
h
enzothiazole
d
s
i Adib,*a Esmail Sheibani,a Long-Guan Zhu,b Hamid Reza Bijanzadehc
a
School of Chemistry, University College of Science, University of Tehran, 14155-6455 Tehran, Iran
Fax +98(21)66495291; E-mail: madib@khayam.ut.ac.ir
b
c
Chemistry Department, Zhejiang University, Hangzhou 310027, P. R. of China
Department of Chemistry, Tarbiat Modarres University, 14115-175 Tehran, Iran
Received 1 August 2008
calmodulin, antiulcer, antiproliferative,9 hypnotic, anxi-
olytic, and anticonvulsant10 activities. Furthermore, some
9H-IBI have been claimed to be serotonin 5-HT2, 5-HT3,11
and corticotropin-releasing factor 1 receptor (CRF1R) an-
tagonists (e.g., 2, Figure 1).12
Abstract: An efficient synthesis of imidazo[2,1-b][1,3]benzothiaz-
oles and 9H-imidazo[1,2-a][1,3]benzimidazoles is described from a
novel multicomponent reaction between 2-aminobenzothiazoles or
2-aminobenzimidazole, benzaldehydes, and imidazoline-2,4,5-tri-
one under solvent-free conditions.
Key words: imidazo[2,1-b][1,3]benzothiazoles, 9H-imidazo[1,2-
a][1,3]benzimidazoles, imidazoline-2,4,5-trione, multicomponent
reactions, solvent-free synthesis, heterocycles
Pr
N
O
NEt2⋅HCl
S
N
N
⋅HCl
CF3
Multicomponent reactions (MCR) have become a signifi-
cant part of today’s arsenal of methods in combinatorial
chemistry due to their valued features such as atom econ-
omy, straightforward reaction design, and the opportunity
to construct target compounds by the introduction of sev-
eral diversity elements in a single chemical event. Typi-
cally, purification of products resulting from MCR is also
simple since all the organic reagents employed are con-
sumed and are incorporated into the target compound.1
Multicomponent reactions, leading to interesting hetero-
cyclic scaffolds, are particularly useful for the construc-
tion of diverse chemical libraries of ‘drug-like’ molecules.
N
N
N
O
2
YM-201627 (1)
an orally active antitumor agent
a CRF1R antagonist
Figure 1 Examples of pharmacologically active IBT and 9H-IBI
So far, several synthetic routes have been reported for the
preparation of these heterocycles. The most common ap-
proaches classified on the basis of the number of ring at-
oms in each of the components being cyclized involve: (i)
single bond formation from [5+0] atom fragments and (ii)
formation of two bonds from [4+1] or [3+2] atom frag-
ments.3,13–16
In recent times, the progress in the field of solvent-free re-
actions is gaining significance because of their high effi-
ciency, operational simplicity, and environmentally
benign processes.2
As far as we know, there is no report concerning the syn-
thesis of these heterocyclic systems by formation of three
bonds. Considering the important biological properties of
these fused tricyclic compounds, as part of our continuing
efforts on the development of new routes for the prepara-
tion of biologically active heterocyclic compounds,17 we
report herein a novel synthesis of these nuclei from
[3+1+1] atom fragments by formation of three bonds.
Thus, 2-aminobenzothiazoles or 2-aminobenzimidazole
3, benzaldehydes 4, and imidazoline-2,4,5-trione 5 under-
go a novel one-pot multicomponent addition reaction to
produce IBT or 9H-IBI 6a–i under solvent-free conditions
(Scheme 1, Table 1).
Imidazo[2,1-b][1,3]benzothiazoles (IBT) and 9H-imida-
zo[1,2-a][1,3]benzimidazoles (9H-IBI), fused tricyclic 6-
5-5 heterocyclic compounds, are of interest because of the
occurrence of these heterocycles in biologically active
compounds, some of which are used in pharmaceutical
preparations.3
Some IBT have been reported as serotonin 5-HT3 receptor
antagonists.4 YM-201627 (1, Figure 1) is an orally active
antitumor agent with selective inhibition of vascular en-
dothelial cell proliferation.5
Compounds having 9H-IBI ring system have been shown
to possess hypotensive, antiaggregating, membrane-stabi-
lizing,6 hypoglycemic, hyperglycemic, spasmolytic,7
antiarrhythmic, antioxidant,8 membranotropic, anti-
After the reaction had been performed at equivalent ratios
of 2-aminobenzothiazole (3, R = H and X = S), 4-methyl-
benzaldehyde (4, Ar = 4-MeC6H4) and 5, the TLC and 1H
NMR analysis of the reaction mixture indicated the for-
mation of the corresponding IBT 6a at nearly 45% yield.
Nearly half of 2-aminobenzothiazole was recovered unre-
acted at the end of the reaction, compared with the amount
SYNLETT 2008, No. 19, pp 2941–2944
x
x
.x
x
.2
0
0
8
Advanced online publication: 12.11.2008
DOI: 10.1055/s-0028-1083623; Art ID: D04308ST
© Georg Thieme Verlag Stuttgart · New York

2942
M. Adib et al.
LETTER
O
O
R
R
X
N
X
N
solvent-free
+
NH2
ArCHO
+
HN
NH
N
200 °C, 5 min
O
Ar
3
4
ArCH
N
5
6
Scheme 1
initially added. Thus, the best results were obtained when Table 1 Synthesis of Imidazo[2,1-b][1,3]benzothiazoles and 9H-
Imidazo[1,2-a][1,3]benzimidazoles 6a–i
the reactions were carried out using the three components
at the 1:2.5:1.5 ratios, respectively (Table 1).18
The reactions were carried out by mixing the amine com-
ponent 3, the aldehyde 4, and imidazoline-2,4,5-trione 5.
N
N
The reaction proceeded at 200 °C and was complete with-
ArHC
N
Ar
in a few minutes and afforded the corresponding IBT or
6
9H-IBI 6 in 90–97% yields.18
The structures of the isolated adducts 6a–i were deduced
Mp
(°C)
Yield
(%)a
6
Ar
1
by IR, H NMR and 13C NMR spectroscopy, mass spec-
N
trometry, and elemental analysis. The mass spectrum of
6a displayed the molecular ion [M+] peak at m/z 381,
which was consistent with the adduct structure. The H
S
1
6a
6b
6c
6d
4-MeC6H4
4-MeOC6H4
3-MeC6H4
4-FC6H4
144–145
134–136
135
92
95
92
97
NMR spectrum of 6a exhibited three sharp singlets, aris-
ing from the two methyl (d = 2.37 and 2.44 ppm) and
aldimine (d = 8.67 ppm) groups along with characteristic
multiplets with appropriate chemical shifts and coupling
constants for the four H atoms of the the six-membered
ring, as well as four doublets for the eigth H atoms of the
N
S
N
S
N
S
N
1
two aryl substituents. The H-decoupled 13C NMR spec-
trum of 6a showed 20 distinct resonances, in agreement
with the suggested structure. Partial assignments of these
resonances are given.18 Single-crystal X-ray analysis con-
clusively confirmed the structure of the isolated products.
An ORTEP diagram of 6a is shown in Figure 2.19
175–176
S
6e
6f
4-MeC6H4
4-FC6H4
194–195
217–219
94
94
N
S
N
H
N
6g
6h
6i
4-FC6H4
264–265
92
93
90
N
H
N
4-MeC6H4
3-MeC6H4
235–238 (dec)
223–226 (dec)
N
H
N
Figure 2 Molecular structure of 6a
N
In summary, we have developed a novel, efficient, one-
pot and multicomponent synthesis of imidazo[2,1-
b][1,3]benzothiazoles and 9H-imidazo[1,2-a][1,3]benz-
imidazoles of potential synthetic and pharmacological in-
terest. Solvent-free conditions, excellent yields of the
products, and use of simple starting materials are the main
a Isolated yields.
Synlett 2008, No. 19, 2941–2944 © Thieme Stuttgart · New York

LETTER
Synthesis of Imidazo[2,1-b][1,3]benzothiazoles
Bijanzadeh, H. R. Tetrahedron Lett. 2007, 48, 1179.
(e) Adib, M.; Sheibani, E.; Mostofi, M.; Ghanbary, K.;
Bijanzadeh, H. R. Tetrahedron 2006, 62, 3435. (f) Adib,
M.; Mahdavi, M.; Mahmoodi, N.; Pirelahi, H.; Bijanzadeh,
H. R. Synlett 2006, 1765. (g) Adib, M.; Ghanbary, K.;
Mostofi, M.; Bijanzadeh, H. R. Tetrahedron 2005, 61,
2645. (h) Adib, M.; Mollahosseini, M.; Yavari, H.; Sayahi,
M. H.; Bijanzadeh, H. R. Synlett 2004, 1086.
2943
advantages of this method. The reactions have been per-
formed under neutral conditions and the substances have
been mixed without any activation or modification. The
simplicity of this method makes it an interesting alterna-
tive to other approaches. Further investigations on the re-
action mechanism, the scope, and the limitations of this
reaction are under way.
(18) Procedure for the Preparation of 2-(4-Methylphenyl)-
N3-[(E)-1-(4-methylphenyl)methylidene]imidazo[2,1-b]-
[1,3]benzothiazol-3-amine (6a)
Acknowledgment
A mixture of 2-aminobenzothiazole (0.30 g, 2 mmol),
4-methylbenzaldehyde (0.60 g, 5 mmol), and imidazoline-
2,4,5-trione (0.34 g, 3 mmol) was stirred at 200 °C for 5 min.
Then, the reaction mixture was cooled to r.t. and the residue
was purified by column chromatography using n-hexane–
EtOAc (1:3) as eluent. The solvent was removed and the
product was recrystallized from n-hexane–EtOAc (1:1). The
product 6a was obtained as yellow crystals; yield 0.70 g
(92%, relative to 2-aminobenzothiazole). IR (KBr): 1603,
1495, 1479, 1379, 1352, 1315, 1175, 1146, 1109, 820, 748
cm–1. 1H NMR (500.1 MHz, CDCl3): d = 2.37, 2.45 (2 × s,
6 H, 2 × CH3), 7.19 (d, J = 7.4 Hz, 2 H, 2 × CH), 7.29–7.32
(m, 3 H, 3 × CH), 7.42 (dd, J = 7.9, 7.4 Hz, 1 H, CH), 7.64–
7.68 (m, 3 H, 3 × CH), 7.76 (d, J = 7.4 Hz, 2 H, 2 × CH), 8.27
(d, J = 8.0 Hz, 1 H, CH), 8.74 (s, 1 H, CH). 13C NMR (125.8
MHz, CDCl3): d = 21.30, 21.70 (2 × CH3), 115.03, 123.79,
124.45, 126.18, 127.32, 128.60, 129.52, 129.70 (8 × CH),
130.27, 131.88, 133.25, 133.36, 133.61, 135.18, 137.10,
142.32, 144.98 (9 × C), 159.89 (CH). MS: m/z (%) = 381
(100) [M+], 366 (10), 289 (4), 251 (85), 134 (16), 103 (7), 91
(14), 77 (7), 65 (5). Anal. Calcd (%) for C24H19N3S (381.50):
C, 75.56; H, 5.02; N, 11.01. Found: C, 75.5; H, 5.2; N, 10.9.
Compound 6d: yellow crystals; yield 0.75 g (97%). IR
(KBr): 1603, 1589, 1528, 1500, 1491, 1454, 1379, 1290,
1225, 1192, 1148, 1092, 845, 752 cm–1. 1H NMR (500.1
MHz, CDCl3): d = 7.09 (dd, 3JFH = 8.6 Hz, 3JHH = 8.7 Hz,
2 H, 2 × CH), 7.20 (dd, 3JFH = 8.6 Hz, 3JHH = 8.7 Hz, 2 H,
2 × CH), 7.35 (dd, J = 8.1, 7.2 Hz, 1 H, CH), 7.45 (dd,
J = 8.1, 7.2 Hz, 1 H, CH), 7.69 (d, J = 7.2 Hz, 1 H, CH), 7.72
(dd, 4JFH = 5.4 Hz, 3JHH = 8.7 Hz, 2 H, 2 × CH), 7.86 (dd,
4JFH = 5.5 Hz, 3JHH = 8.7 Hz, 2 H, 2 × CH), 8.24 (d, J = 8.1
Hz, 1 H, CH), 8.67 (s, 1 H, CH). 13C NMR (125.8 MHz,
CDCl3): d = 114.94 (CH), 115.87 (d, 2JFC = 21.5 Hz, CH),
116.27 (d, 2JFC = 22.1 Hz, CH), 123.93, 124.71, 126.29 (3 ×
CH), 129.34 (d, 3JFC = 7.9 Hz, CH), 130.30 (C), 130.56 (d,
3JFC = 8.8 Hz, CH), 130.82 (d, 4JFC = 3.3 Hz, C), 132.30 (d,
4JFC = 3.2 Hz, C), 132.56, 133.21, 134.89, 145.43 (4 × C),
158.47 (CH), 162.20 (d, 1JFC = 247.3 Hz, CF), 165.05 (d,
1JFC = 253.7 Hz, CF). MS: m/z (%) = 389 (98) [M+], 350
(32), 326 (8), 255 (100), 229 (27), 201 (13), 134 (37), 107
(15), 90 (9). Anal. Calcd (%) for C22H13F2N3S (389.43): C,
67.85; H, 3.36; N, 10.79. Found: C, 67.8; H, 3.4; N, 10.7.
Compound 6g: yellow crystals; yield: 0.68 g (92%). IR
(KBr): 3290 (NH), 1601, 1585, 1528, 1510, 1493, 1450,
1339, 1232, 1225, 1196, 1150, 1094, 839, 768 cm–1.
1H NMR (500.1 MHz, DMSO-d6): d = 7.19 (dd, J = 7.8, 7.6
Hz, 1 H, CH), 7.25 (dd, 3JFH = 8.6 Hz, 3JHH = 8.7 Hz, 2 H,
2 × CH), 7.31 (dd, J = 7.8, 7.6 Hz, 1 H, CH), 7.37 (dd,
3JFH = 8.6 Hz, 3JHH = 8.7 Hz, 2 H, 2 × CH), 7.43 (d, J = 7.8
Hz, 1 H, CH), 7.71 (d, J = 8.0 Hz, 1 H, CH), 8.04 (dd,
4JFH = 5.3 Hz, 3JHH = 8.7 Hz, 2 H, 2 × CH), 8.19 (dd,
4JFH = 5.4 Hz, 3JHH = 8.7 Hz, 2 H, 2 × CH), 8.86 (s, 1 H, CH),
12.00 (br, 1 H, NH). 13C NMR (125.8 MHz, DMSO-d6):
d = 112.04, 112.36 (2 × CH), 115.04 (d, 2JFC = 21.4 Hz, CH),
116.00 (d, 2JFC = 22.0 Hz, CH), 119.84, 123.61 (2 × CH),
124.98, 127.37 (2 × C), 129.18 (d, 3JFC = 7.9 Hz, CH),
This research was supported by the Research Council of University
of Tehran as a research project (6102036/1/03).
References and Notes
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(17) (a) Adib, M.; Mohammadi, B.; Bijanzadeh, H. R. Synlett
2008, 177. (b) Adib, M.; Aali Koloogani, S.; Abbasi, A.;
Bijanzadeh, H. R. Synthesis 2007, 3056. (c) Adib, M.;
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Synlett 2008, No. 19, 2941–2944 © Thieme Stuttgart · New York

2944
M. Adib et al.
LETTER
130.03 (d, 3JFC = 8.7 Hz, CH), 131.22 (d, 4JFC = 3.3 Hz, C),
133.29 (d, 4JFC = 3.2 Hz, C), 136.45, 138.98, 148.09 (3 × C),
150.49 (CH), 162.41 (d, 1JFC = 247.9 Hz, CF), 164.95 (d,
1JFC = 252.5 Hz, CF). MS: m/z (%) = 372 (19) [M+], 360
(15), 326 (97), 238 (91), 229 (23), 196 (100), 133 (33), 118
(43), 107 (19), 95 (35), 79 (44), 69 (16). Anal. Calcd (%) for
C22H14F2N4 (372.38): C, 70.96; H, 3.79; N, 15.05. Found: C,
71.0; H, 3.8; N, 14.9.
(12) Å, b = 7.5112 (7) Å, c = 21.2243 (20) Å, b = 91.626
(2)°, V = 2033.03 (3) Å3, T = 295 (2) K, Z = 4, Dcalcd
=
1.25 g cm–3, m = 0.173 mm–1, 2245 observed reflections,
final R1 = 0.079, wR2 = 0.149 and for all data R1 = 0.137,
wR2 = 0.172. CCDC 671151 contains the supplementary
crystallographic data for the structure reported in this paper.
These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via
(19) Selected X-ray Crystallographic Data for Compound 6a
C24H19N3S, monoclinic, space group = P21/n, a = 12.7579
www.ccdc.cam.ac.uk/data_request/cif.
Synlett 2008, No. 19, 2941–2944 © Thieme Stuttgart · New York