Synthesis of 2-benzylimidazo[2,1-b][1,3]benzothiazoles through palladium-catalyzed heteroannulation of acetylenic compounds

Article abstract of DOI:10.1016/j.tetlet.2008.07.163

The reaction of 2-imino-3-(2-propynyl)-1,3-benzothiazole with various iodobenzenes in the presence of a palladium catalyst leads to the production of 2-benzylimidazo[2,1-b][1,3]benzothiazoles.

Full text of DOI:10.1016/j.tetlet.2008.07.163

Tetrahedron Letters 49 (2008) 6188–6191
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Tetrahedron Letters
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Synthesis of 2-benzylimidazo[2,1-b][1,3]benzothiazoles through
palladium-catalyzed heteroannulation of acetylenic compounds
a
a
a
Mohammad Bakherad a, , Hossein Nasr-Isfahani , Ali Keivanloo , Golnaz Sang
*
a Department of Chemistry, School of Sciences, Shahrood University of Technology, Shahrood, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of 2-imino-3-(2-propynyl)-1,3-benzothiazole with various iodobenzenes in the presence
of a palladium catalyst leads to the production of 2-benzylimidazo[2,1-b][1,3]benzothiazoles.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 7 February 2008
Revised 22 July 2008
Accepted 30 July 2008
Available online 3 August 2008
Keywords:
Sonogashira coupling
Aryl iodide
Benzothiazole
Pd-catalyzed
Imidazo benzothiazoles
Imidazobenzothiazole derivatives are common substructures of
synthetic molecules displaying important medicinal activities.1
Their core ring system is present in numerous cardiotonic2 and
immunosuppressive3 drugs. Considering the potent bioactivities
of compounds possessing an imidazobenzothiazole core, the devel-
opment of a new strategy to synthesize efficiently 2-benzyl-
imidazo[2,1-b][1,3]benzothiazoles has attracted our attention.
The Pd–Cu-catalyzed cross-coupling reaction of terminal acetyl-
enes with sp2-C halides provides a useful method for synthesizing
conjugated acetylenic compounds, which are an important class of
molecules.4 Several groups have described annulation reactions in
heterocyclization-based Sonogashira coupling.5 We were intrigued
by the prospect of applying this methodology to the synthesis of
other heterocyclic systems.
at room temperature gave 2-substituted imidazo[2,1-b][1,3]benzo-
thiazoles 3a–i in moderate to high yields (Scheme 1, Table 1). The
reactions were carried out under an argon atmosphere, and DMF
and triethylamine were degassed prior to use.
Mechanistically, the formation of 2-benzylimidazo[2,1-b]-
[1,3]benzothiazoles involves the following steps (as shown in
Scheme 1): (i) formation of ArPdI [B] through oxidative addition
of Pd(0) [A] to ArI;8 (ii) transmetallation of ArPdI with the Cu salt
of [C], generating the alkynyl palladium species [D]; (iii) extrusion
of Pd(0) to yield the alkynes [E]; (iv) isomerization to the allenic
intermediates9 [F] which then cyclize to products 3a–i.
The presence of electron-withdrawing groups such as –NO2, –Cl
or –CN on the aryl iodide was essential for successful reaction.
When p-iodoanisole was used as the aryl iodide, Sonogashira cou-
pling did not occur. It is also noteworthy that in the case of iodo-
benzene as the aryl iodide, the cyclization occurred without any
involvement of the aryl iodide. The product of this reaction was
identified as 2-methylimidazo[2,1-b][1,3]benzothiazole 4 (Scheme
2).7
In conclusion, we have developed an efficient and useful meth-
od for the synthesis of 2-substituted imidazo[2,1-b][1,3]benzo-
thiazoles. To our knowledge, this is the first reported general
procedure for the palladium–copper-catalyzed synthesis of
2-substituted imidazobenzothiazoles.
Although several methods have been reported for the synthesis
of imidazo[2,1-b][1,3]benzothiazoles,6 a literature survey showed
no reports on the Pd–Cu-catalyzed preparation of this system.
To introduce a benzyl substituent to imidazo[2,1-b][1,3]benzo-
thiazole, our retrosynthetic analysis implicated the use of propar-
gyl bromide, 2-aminobenzothiazole and an aryl iodide as the
starting materials, with a palladium-catalyzed cross coupling-
cyclization as the key step (Fig. 1).
Treatment of 2-imino-3-(2-propynyl)-1,3-benzothiazole 17 in
DMF with aryl iodides 2a–i and triethylamine in the presence of
bis(triphenylphosphine)palladium(II) chloride and cuprous iodide
Synthesis of 2-substituted imidazo[2,1-b][1,3]benzothiazoles
3a–i: A mixture of the aryl iodides 2a–i (0.75 mmol), (PPh3)2PdCl2
(0.05 mmol), CuI (0.1 mmol), and triethylamine (3 mmol) was stir-
red in DMF (5 mL) at room temperature under an argon atmo-
sphere. 2-Imino-3-(2-propynyl)-1,3-benzothiazole 1 (1.27 mmol,
* Corresponding author. Fax: +98 2733335441.
E-mail address: mbakherad@shahroodut.ac.ir (M. Bakherad).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.163

M. Bakherad et al. / Tetrahedron Letters 49 (2008) 6188–6191
6189
CH
CAr
CH2Ar
N
S
N
S
N
S
N
ArI
NH
NH
+
N
S
NH2
BrH2C
C
CH
+
Figure 1. Reterosynthetic analysis of imidazo[2,1-b][1,3]benzothiazole.
(PPh3)2PdCl2
a
ArI
2a-i
Pd(0)
ArPdI
[A]
[B]
CPdAr
CH
CCu
C
C
C
N
N
S
N
S
b
NH
NH
NH
S
CuI
1
[C]
[D]
Pd(0)
C
+
Et3NH
Ar
C
CH2Ar
CAr
C
N
N
c
d
NH
N
N
S
S
NH
S
[E]
3a-i
[F]
Scheme 1. A plausible mechanism for the formation of 2-benzylimidazo[2,1-b][1,3] benzothiazoles at room temprature. Reagents and conditions: (a) Reduction of Pd(II) to
Pd(0) with alkyne and Et3N; (b) CuI, Et3N; (c) isomerization to an allene with CuI, Et3N; (d) nucleophilic attack on the allene (F) to generate the 2-benzylimidazo[2,1-b][1,3]
benzothiazoles 3a–i.
0.34 mg) was then added and the mixture was stirred at room tem-
perature for 20 h. After completion of the reaction, the resulting
solution was concentrated in vacuo, and the crude product was
subjected to silica gel column chromatography using CHCl3/CH3OH
(95:5) as the eluent to afford the pure product (Table 1).
Compound 3c: 1H NMR d (500 MHz, DMSO-d6): 4.38 (s, 2H,
CH2), 7.38–8.18 (m, 8H, ArH), 8.20 (s, 1H, CH of imidazole); 13C
NMR
125.37, 127.26, 127.95, 128.87, 130.80, 131.13, 133.15, 140.04,
147.75, 153.82; IR,
(KBr disc): 1500, 1345 cmÀ1; MS (EI) m/z,
309 (M+, 100), 262(96), 187(55), 131(40), 108(42). Anal. Calcd for
16H11N3O2S: C, 62.12; H, 3.58; N, 13.58; S, 10.37. Found: C,
d (125 MHz, DMSO-d6): 34.26, 114.75, 122.70, 123.02,
m
Compound 3a: 1H NMR d (500 MHz, DMSO-d6): 4.37 (s, 2H,
CH2), 7.37–8.00 (m, 8H, ArH), 8.2 (s, 1H, CH of imidazole); 13C
C
NMR
d
(125 MHz, DMSO-d6): 34.08, 114.42, 122.12, 122.70,
62.43; H, 3.70; N, 13.76; S, 10.56.
123.11, 125.43, 127.61, 128.93, 129.27, 130.67, 131.13, 132.02,
Compound 3d: 1H NMR d (500 MHz, DMSO-d6): 2.06 (s, 3H,
CH3), 4.35 (s, 2H, CH2), 7.19–7.90 (m, 7H, ArH), 8.00 (s, 1H, CH of
134.30, 139.34, 148.20, 153.25; IR,
m ;
(KBr disc): 1490, 1340 cmÀ1
MS (EI) m/z, 309 (M+, 45), 308(63), 263(100), 186(53), 131(34),
108(47). Anal. Calcd for C16H11N3O2S: C, 62.12; H, 3.58; N, 13.58;
S, 10.37. Found: C, 62.54; H, 3.72; N, 13.82; S, 10.16.
imidazole); 13C NMR
d
(125 MHz, DMSO-d6): 20.12, 33.91,
114.15, 122.21, 122.55, 122.96, 123.90, 126.02, 127.41, 127.86,
128.97, 130.37, 130.95, 133.32, 139.25, 148.03, 153.56; IR,
m (KBr
Compound 3b: 1H NMR d (500 MHz, DMSO-d6): 4.18 (s, 2H,
CH2), 7.39–7.81 (m, 4H, ArH), 7.97–8.09 (m, 4H, ArH), 8.20 (s, 1H,
CH of imidazole); 13C NMR d (125 MHz, DMSO-d6): 34.20, 114.62,
122.40, 123.01, 126.10, 127.61, 128.05, 128.37, 129.21, 130.22,
disc): 1520, 1340 cmÀ1; MS (EI) m/z 323 (M+, 100), 276(49),
187(24), 150(21), 131(37), 39(28). Anal. Calcd for C17H13N3O2S:
C, 63.14; H, 4.05; N, 12.99; S, 9.92. Found: C, 62.78; H, 3.86; N,
12.63; S, 9.73.
130.76, 133.87, 138.20, 140.09, 146.80, 154.01; IR,
m
(KBr disc):
Compound 3e: 1H NMR d (500 MHz, DMSO-d6): 4.33 (s, 2H,
1510, 1340 cmÀ1; MS (EI) m/z, 309 (M+, 100), 261(63), 187(42),
130(24), 109(39). Anal. Calcd for C16H11N3O2S: C, 62.12; H3x,
3.58; N, 13.58; S, 10.37. Found: C, 61.73; H, 3.30; N, 13.25; S, 10.11.
CH2), 7.52–7.99 (m, 7H, ArH), 8.11 (s, 1H, CH of imidazole); 13C
NMR
d (125MHz, DMSO-d6): 33.77, 114.71, 123.15, 123.55,
125.87, 127.23, 128.20, 129.10, 130.17, 130.65, 131.35, 132.71,

6190
M. Bakherad et al. / Tetrahedron Letters 49 (2008) 6188–6191
m
(KBr disc): 1490 cmÀ1; MS (EI)
Table 1
134.32, 139.77, 149.60, 153.20; IR,
m/z, 345 (M+37Cl, 14), 343 (M+35Cl, 46), 326(100), 298(68), 263(93),
203(34), 161(47), 131(51), 108(39). Anal. Calcd for C16H10ClN3O2S:
C, 55.90; H, 2.93; N, 12.22; S, 9.33. Found: C, 55.59; H, 2.66; N,
12.07; S, 9.10.
Melting points and yields of 2-benzylimidazo[2,1-b][1,3]benzothiazoles 3a–i
Product
Ar
Mp (°C)
Yield (%)
NO
2
3a
281–282
74
Compound 3f: 1H NMR d (500 MHz, DMSO-d6): 4.34 (s, 2H, CH2),
7.38–8.1 (m, 7H, ArH), 8.17 (s, 1H, CH of imidazole); 13C NMR d
(125 MHz, DMSO-d6): 34.10, 114.21, 122.67, 123.09, 123.67,
126.20, 127.62, 128.80, 129.18, 130.70, 131.12, 132.15, 134.48,
139.23, 150.02, 154.10; IR,
m
(KBr disc): 1510, 1340 cmÀ1; MS(EI)
m/z, 345 (M+37Cl, 20), 343 (M+35Cl, 56), 308(53), 297(100),
3b
3c
279–280
289–290
72
87
261(43), 186(47), 170(23), 133(41), 107(27). Anal. Calcd for
NO
2
C16H10ClN3O2S: C, 55.90; H, 2.93; N, 12.22; S, 9.33. Found: C,
55.73; H, 2.77; N, 12.36; S, 9.15.
Compound 3g: 1H NMR d (500 MHz, DMSO-d6): 4.35 (s, 2H,
CH2), 7.38–8.07 (m, 7H, ArH), 8.32 (s, 1H, CH of imidazole); 13C
NMR
d (125 MHz, DMSO-d6): 33.87, 114.85, 122.78, 123.67,
NO
125.76, 126.88, 127.61, 129.17, 129.57, 130.75, 131.20, 135.02,
2
135.47, 139.34, 148.45, 153.27; IR,
m ;
(KBr disc): 1510, 1335 cmÀ1
MS (EI) m/z, 345 (M+37Cl, 12), 343 (M+35Cl, 31), 298(100),
262(68), 201(27), 132(43), 109(35). Anal. Calcd for C16H10ClN3O2S:
C, 55.90; H, 2.93; N, 12.22; S, 9.33. Found: C, 55.67; H, 2.69; N,
11.97; S, 9.41.
CH
3
3d
3e
280–281
292–293
70
85
Compound 3h: 1H NMR d (500 MHz, DMSO-d6): 4.11 (s, 2H,
CH2), 7.12–7.69 (m, 5H, ArH), 7.85 (d, J = 5Hz, 1H, ArH), 7.96–
8.02 (m, 2H, ArH), 8.10 (s, 1H, CH of imidazole); 13C NMR d
(125 MHz, DMSO-d6): 34.15, 113.30, 114.56, 120.02, 122.65,
125.83, 127.32, 128.85, 129.31, 130.36, 130.74, 131.16, 139.37,
NO
2
NO
2
141.43, 154.17; IR,
22), 286(32), 261(45), 187(100), 130(28), 116(23). Anal. Calcd for
17H11N3S: C, 70.56; H, 3.83; N, 14.52; S, 11.08. Found: C, 70.82;
m
(KBr disc): 2200 cmÀ1; MS (EI) m/z 289 (M+,
Cl
C
H,3.92; N, 14.70; S, 11.26.
Cl
Compound 3i: 1H NMR d (500 MHz, DMSO-d6): 3.86 (s, 3H, CH3),
4.15 (s, 2H, CH2), 7.39–8.00 (m, 8H, ArH), 8.20 (s, 1H, CH of imidaz-
ole); 13C NMR d (125 MHz, DMSO-d6): 34.15, 51.23, 114.76, 122.37,
125.64, 127.43, 128.32, 129.07, 129.49, 130.15, 130.68, 132.78,
3f
295–296
286–287
67
55
m
(KBr disc): 1710 cmÀ1; MS
NO2
138.25, 140.10, 154.08, 167.23; IR,
(EI) m/z 322 (M+,100), 306(87), 262(43), 186(44), 170(24),
147(23), 131(33). Anal. Calcd for C18H14N2O2S: C, 67.06; H, 4.38;
N, 8.69; S, 9.95. Found: C, 66.85; H, 4.22; N, 8.90; S, 9.72.
3g
NO
2
Acknowledgement
Cl
The authors would like to thank the Research Council of Shah-
rood University of Technology for the support of this work.
3h
273–274
290–291
77
75
References and notes
CN
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3i
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COOMe
CH
C
CH3
N
N
[(PPh3)2PdCl2]
Et3N, CuI, DMF
N
NH
PhI
+
S
S
1
4
Scheme 2. Synthesis of 2-methylimidazo[2,1-b][1,3]benzothiazole.

M. Bakherad et al. / Tetrahedron Letters 49 (2008) 6188–6191
6191
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