Pd-Cu catalyzed heterocyclization during Sonogashira coupling: Synthesis of 3-benzylthiazolo[3,2-a]benzimidazole

Article abstract of DOI:10.1016/j.tetlet.2004.05.094

The reaction of 2-mercaptopropargyl benzimidazole with various iodobenzenes catalyzed by Pd-Cu leads to the formation of 3-benzylthiazolo[3,2-a] benzimidazoles.

Full text of DOI:10.1016/j.tetlet.2004.05.094

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5747–5749
Pd–Cu catalyzed heterocyclization during Sonogashira coupling:
synthesis of 3-benzylthiazolo[3,2-a]benzimidazole
b
b
Majid M. Heravi,a,b, Ali Keivanloo, Mohammad Rahimizadeh,
*
Mehdi Bakavolib and Mitra Ghassemzadehc
aDepartment of Chemistry, School of Sciences, Azzahra University, Vanak, Tehran, Iran
bDepartment of Chemistry, School of Sciences, Ferdowsi University of Mashhad, Mashhad, Iran
cChemistry and Chemical Engineering Research Center of Iran, PO Box 14335-186, Tehran, Iran
Received 16 February 2004; revised 26 April 2004; accepted 14 May 2004
Available online 10 June 2004
Abstract—The reaction of 2-mercaptopropargyl benzimidazole with various iodobenzenes catalyzed by Pd–Cu leads to the for-
mation of 3-benzylthiazolo[3,2-a]benzimidazoles.
Ó 2004 Elsevier Ltd. All rights reserved.
Benzimidazole derivatives are of wide interest because of
their diverse biological activities and clinical applica-
tions. Their core ring system is present in numerous
antiparasitic, fungicide and anti-inflammatory drugs.1
Various thiazole derivatives are known to exhibit
pharmacological activities.2 Fused thiazoles are of
importance not only as medicinal agents but also as
organic functional materials such as fluorescent dyes.3
to the synthesis of other systems in particular hetero-
cyclic systems.
Although, several methods have been reported6 for the
synthesis of thiazolo[3,2-a]benzimidazoles, a literature
survey showed no reference concerning the use of a Pd–
Cucatalyzed preparation of this system.
We have recently reported the synthesis of various het-
erocyclic systems via a Sonogashira cross-coupling and a
subsequent exocyclic cyclization.7 In this communica-
tion we wish to extend our strategy to the synthesis of
substituted 3-benzylthiazolo[3,2-a]benzimidazoles.
The Pd–Cucatalyzed cross-coupling reaction of termi-
nal acetylenes with sp2-C halides provides a useful
method for synthesizing conjugated acetylenic com-
pounds, which are an important class of molecules.4
Several groups have also described annulation in hetero-
cyclization based Sonogashira coupling.5 We were
intrigued by the prospect of applying this methodology
2-Mercaptobenzimidazole 1 was reacted with propargyl
bromide in refluxing EtOH in the presence of NH4OH
Y
H
X
I
H
H
S
H
S
Y
N
N
N
S
N
N
H
N
X
4
3
2
1
* Corresponding author. E-mail: mmheravi@azzahra.ac.ir
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.094

5748
M. M. Heravi et al. / Tetrahedron Letters 45 (2004) 5747–5749
Table 1. Melting points and yields of 3-benzylthiazolo[3,2-a]benzi-
midazoles 4a–e
aYield (%)
Product
ArI
Mp (°C)
X
Y
H
H
4a
4b
4c
4d
4e
NO2
NO2
H
H
Cl
191–2
180–1
147–8
209–10
214–6
82
85
78
79
81
N
N
N
N
[(PPh3)2PdCl2]
Et3N, CuI, DMF
NO2
H
S
S
+
PhI
CN
Cl
CN
5 (70%)
a Yields refer to isolated products.
Et3N, DMF
reflux
to yield 2-propargylmercaptobenzimidazole 2.8 When 2
was treated in DMF with aryl halides 3a–e and trieth-
ylamine in the presence of bis(triphenylphosphine)palla-
dium chloride and copper iodide at room temperature,
3-benzylthiazolo-[3,2-a]benzimidazoles 4 were obtained
in good to high yields (Table 1). The reactions
must be carried out under an argon atmosphere
and the mixture of DMF and triethylamine must be de-
gassed prior to use. Bis(triphenylphosphine) palladium
chloride and triethylamine were found to be the catalyst
and base of the choice. However, cuprous iodide was
found to be an essential co-catalyst. Reactions carried
out with either copper(I) iodide or palladium(II) chloride
as catalysts alone led to very poor yields of products.
N
S
N
4f, X,Y=H (76%)
Scheme 2.
to obtain 4 (X, Y ¼ H). When p-iodotoluene 3 (X,
Y ¼ Me) was used as the aryl iodide, Sonogashira cou-
pling took place, but cyclization in DMF/Et3N under
reflux conditions, even after a prolonged reaction time,
could not be achieved.
The mechanism of the reaction is illustrated in Scheme
1. Most probably a two step process occurs: first a
standard Sonogashira coupling and known Pd(II) cat-
alyzed intermolecular cyclization of the nucleophilic
nitrogen moiety onto the triple bond followed by base-
induced aromatization.
In conclusion an efficient and extremely useful meth-
odology for the synthesis of thiazolo[3,2-a]benzimid-
azoles has been reported.
The presence of electron withdrawing groups such as
–NO2, –Cl, –CN on the aryl iodide seems to be essential.
When PhI was used as the aryl halide, only a small
amount of product (4, X, Y ¼ H) was isolated by col-
umn chromatography. To establish the mechanism, the
main product of this reaction was separated by column
chromatography and identified as 2-[3-phenylpropargyl-
mercapto]benzimidazole 5 (Scheme 2). This compound
was cyclized and aromatized by refluxing in DMF/Et3N
1. Experimental
1.1. Synthesis of 3-substituted thiazolo[3,2-a]benzimid-
azole. General reaction conditions
A mixture of the aryl iodide (0.75 mmol), (PPh3)2PdCl2
(0.025 mmol), CuI (0.055 mmol) and triethylamine
Ar
H
N
H
N
Sonogashira coupling
+ ArI
S
S
[(PPh3)2PdCl2]
Et3N,CuI,DMF
N
N
Pd(II)
ArCH
N
H
S
ArCH
+
H
CH2Ar
(Et3NH)
Et3N
N
N
N
S
N
S
N
4
Scheme 1.

M. M. Heravi et al. / Tetrahedron Letters 45 (2004) 5747–5749
5749
(2 mmol) was stirred in DMF (25 mL) at room temper-
product. Yield 70%; mp 144–5 °C; 1H NMR
d
ature under an argon atmosphere. 2-Propargylmercapto-
benzimidazole (1.27 mmol) was then added and the
mixture was stirred at room temperature for 24 h. After
completion of the reaction, water (5 mL) was added and
the mixture was extracted with CHCl3. The chloroform
layer was separated and evaporated to dryness and the
crude was directly subjected to column chromatography
using CHCl3–hexane 80:20 as eluent to afford the pure
product (Table 1).
(100 MHz, CDCl3): 4.26 (s, 2H, CH2), 7.17–7.48 (mÀ, 19H,
~
ArH); IR, t (KBr disc): 3059, 2500, 1416, 1278 cm
.
1.3. Synthesis of 3-benzthiazolo[3,2-a]benzimidazole 4f
Compound 5 was dissolved in triethylamine (2 mmol)
and DMF (3 mL). The reaction mixture was refluxed for
3 h. After completion of the reaction, water (5 mL) was
added and the mixture extracted with CHCl3. The
chloroform layer was separated and evaporated to
dryness. The crude was directly subjected to column
chromatography using CHCl3 as eluent to afford the
1
1.1.1. Selected data for 4a. Mp 191–2 °C; yield: 82%; H
NMR d (100 MHz, CDCl3): 4.51 (s, 2H, CH2), 6.25 (s,
1H, CH of thiazole), 7.12–7.51 (m, 4H, ArH), 7.78 (d,
J ¼ 8:2 Hz, 2H, ArH), 8.21 (d, J ¼ 8:2 Hz, 2H, ArH);
1
title compound. Yield 76%; mp 82–3 °C; H NMR d
(100 MHz, CDCl3): 4.37 (s, 2H, CH2), 6.14 (s, 1H, CH
IR, t (KBr disc): 1522, 1349 cmÀ1; MS, m=z, 309.
of thiazole), 7.12–7.80 (m, 9H, ArH); IR, t (KBr disc):
~
~
3063 cmÀ1; MS, m=z, Mþ 264.
1
1.1.2. Selected data for 4b. Mp 180–1 °C; yield: 85%; H
NMR d (100 MHz, DMSO-d6): 4.76 (s, 2H, CH2), 6.67
(s, 1H, CH of thiazole), 7.16–7.74 (m, 5H, ArH), 8.15
(dd, J ¼ 9:3 Hz, 1H, ArH), 8.4 (d, J ¼ 2:2 Hz, 1H,
343, Mþ2 345 (¼ 37Cl).
References and notes
ArH); IR, t (KBr disc): 1524, 1346 cmÀ1; MS, m=z, Mþ
~
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Lonn, U.; Lonn, S. Eur. J. Biochem. 1987, 164, 541; (c)
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1
1.1.3. Selected data for 4c. Mp 147–8 °C; yield: 78%; H
NMR d (100 MHz, CDCl3): 4.78 (s, 2H, CH2), 6.16 (s,
1H, CH of thiazole), 7.12–7.56 (m, 6H, ArH), 7.77 (d,
J ¼ 7:8 Hz, 1H, ArH), 8.2 (d, J ¼ 7:4 Hz, 1H, ArH); IR,
t (KBr disc): 1527, 1340 cmÀ1; MS, m=z, 309.
~
1.1.4. Selected data for 4d. Mp 209–10 °C; yield: 79%; 1H
NMR d (100 MHz, DMSO-d6): 4.67 (s, 2H, CH2), 6.78
4. Sonogashira, K. J. Organomet. Chem. 2002, 653, 46, and
references cited therein.
~
(s, 1H, CH of thiazole), 7.15–7.89 (m, 8H, ArH); IR, t
(KBr disc): 2232 cmÀ1; MS, m=z, Mþ 289.
5. (a) Amjad, M.; Knight, D. W. Tetrahedron Lett. 2004, 45,
539; (b) Kadnikov, D. V.; Larock, R. C. J. Organomet.
Chem. 2003, 687, 425; (c) Pal, M.; Subramanian, V.;
Yeleswarapu, K. R. Tetrahedron Lett. 2003, 44, 8221; (d)
Herndon, J. W.; Zhang, Y.; Wang, A. J. Organomet. Chem.
2001, 634, 1; (e) Yao, T.; Larock, R. C. Tetrahedron Lett.
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6. (a) Badr, M. Z. A.; Mahmoud, A. M.; Mahjoub, S. A.;
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Allan, J. A. J. Org. Chem. 1956, 21, 24; (c) Haru, O.;
Suneo, I. T.; Kikuchi, K. J. Heterocycl. Chem. 1969, 6, 797;
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Silicon 2002, 177, 2491; (b) Heravi, M. M.; Keivanloo, A.;
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A.; Rahimizadeh, M.; Bakavoli, M.; Ghassemzadeh, M. Z.
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1
1.1.5. Selected data for 4e. Mp 214–6 °C; yield: 81%; H
NMR d (100 MHz, DMSO-d6): 4.76 (s, 2H, CH2), 6.58
(s, 1H, CH of thiazole), 7.20–7.84 (m, 6H, ArH), 8.17 (d,
À1
~
J ¼ 2 Hz, 2H, ArH); IR, t (KBr disc): 2210 cm ; MS,
m=z, Mþ 323, M2þ 325 (¼ 37Cl).
1.2. Synthesis of 2-[3-phenylpropargyl]mercaptobenzimid-
azole 5
A mixture of iodobenzene (0.75 mmol), (PPh3)2PdCl2
(0.025 mmol), CuI (0.055 mmol) and triethylamine
(2 mmol) was stirred in DMF (25 mL) at room temper-
ature under an argon atmosphere. 2-Propargylmercapto-
benzimidazole (1.27 mmol) was then added and the
mixture was stirred at room temperature for 24 h. After
completion of the reaction, water (5 mL) was added and
the mixture was extracted with CHCl3. The chloroform
layer was separated and evaporated to dryness and the
crude was directly subjected to column chromatography
using CHCl3–hexane 80:20 as eluent to afford the pure
8. Balasubramanian, K. K.; Venugopalan, B. Tetrahedron
Lett. 1974, 15, 2643.