Synthesis of benzimidazo[2,1-b]benzothiazole derivatives through sequential Cu-catalyzed domino coupling and Pd-catalyzed Suzuki reaction

Article abstract of DOI:10.1016/j.tetlet.2014.04.070

A variety of benzo[d]benzo[4,5]imidazo[2,1-b]thiazoles were efficiently and conveniently synthesized from the Cu-catalyzed domino coupling of o-dihaloarenes with 2-mercaptobenzimidazoles. The reaction is also applicable to a series of multi-functional substrates, affording the halo-containing products with excellent selectivity. The brominated products can further react with arylboronic acids under Pd catalysis to furnish the aryl-substituted benzimidazo[2,1-b]benzothiazole derivatives.

Full text of DOI:10.1016/j.tetlet.2014.04.070

Accepted Manuscript
Synthesis of benzimidazo[2,1-b]benzothiazole derivatives through sequential
Cu-catalyzed domino coupling and Pd-catalyzed Suzuki reaction
Jilong Gao, Jiaoyan Zhu, Lubin Chen, Yingying Shao, Jiaqi Zhu, Yijia Huang,
Xiaoxia Wang, Xin Lv
PII:
S0040-4039(14)00695-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.070
TETL 44532
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
31 December 2013
11 April 2014
17 April 2014
Please cite this article as: Gao, J., Zhu, J., Chen, L., Shao, Y., Zhu, J., Huang, Y., Wang, X., Lv, X., Synthesis of
benzimidazo[2,1-b]benzothiazole derivatives through sequential Cu-catalyzed domino coupling and Pd-catalyzed
Suzuki reaction, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.04.070
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Synthesis of benzimidazo[2,1-b]benzothiazole
derivatives through sequential Cu-catalyzed
domino coupling and Pd-catalyzed Suzuki
reaction
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Jilong Gao, Jiaoyan Zhu, Lubin Chen, Yingying Shao, Jiaqi Zhu, Yijia Huang, Xiaoxia Wang and Xin Lv*

1
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
Synthesis of benzimidazo[2,1-b]benzothiazole derivatives through sequential Cu-
catalyzed domino coupling and Pd-catalyzed Suzuki reaction
Jilong Gao, Jiaoyan Zhu, Lubin Chen, Yingying Shao, Jiaqi Zhu, Yijia Huang, Xiaoxia Wang and Xin Lv∗
Zhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004,
People’s Republic of China
L /ET OAC (15:1 → 8:1, V:V) AS
ABSTRACT
E L UE NT T ARTICLE INFO
Article history:
Received
A variety of benzo[d]benzo[4,5]imidazo[2,1-b]thiazoles were efficiently and conveniently
synthesized from the Cu-catalyzed domino coupling of o-dihaloarenes with 2-
mercaptobenzimidazoles. The reaction is also applicable to a series of multi-functional
Received in revised form
Accepted
Available online
substrates, affording the halo-containing products with excellent selectivity. The brominated
products can further react with arylboronic acids under Pd catalysis to furnish the aryl-
Keywords:
substituted benzimidazo[2,1-b]benzothiazole derivatives.
Benzimidazo[2,1-b]benzothiazole
Cu-catalyzed
Domino
Coupling
2009 Elsevier Ltd. All rights reserved.
Heterocycle
Imidazo[1,2-b]thiazoles have attracted considerable attention,
since they can be employed as antitumor,1 antidiabetic,2
antitubercular3 and anti-cardiovascular4 agents. As a subclass of
imidazo[2,1-b]benzothiazole derivatives,5 benzo[d]benzo[4,5]-
imidazo[2,1-b]thiazoles, which incorporate benzimidazole and
benzothiazole moieties, might possess interesting biological
activities and be utilized as drug candidates in therapeutic areas.
Although benzimidazo[2,1-b]benzothiazole derivatives may play
important roles in medicinal chemistry, efficient synthetic routes
to them are rarely documented. DeJongh et al. found that
benzimidazo[2,1-b]benzothiazole could be prepared from 1-(2-
benzothiazolyl)-benzotriazole using photochemical method.6
Another method to access such polycyclic molecules is the SNAr
reaction of 2-(2,6-dinitro-4-trifluoromethylphenylthio)benz-
imidazole with 2-mercaptobenzimidazole.7 These methods
usually require special starting materials and tedious procedures,
and suffer from the low efficiency and narrow scopes. Ma and
coworkers developed a one-pot synthesis of benzimidazo[2,1-
b]thiazoles from the SNAr reactions of o-halonitroarenes/o-
dihaloarenes with 2-mercaptoimidazoles.8 The protocol is
efficient and convenient. However, substrates with strong
electron-withdrawing groups on the arenes or 2-pyridinyl
halorides were required. Such a drawback may restrict the
application scope of this domino method.
formation.10 And recently, the domino reactions involving Cu-
catalyzed coupling as the key steps have aroused increasing
interest in modern heterocycle synthesis.11 However, the reports
represent the Cu-mediated one-pot generation of imidazo[2,1-
b]benzothiazoles are still rare. Recently, Wu et al. found that the
Cu-catalyzed cascade reaction of 2-iodoaniline and 2-
iodobenzothiazole gave benzimidazo[2,1-b]benzothiazole,12
whereas no systematic studies were demonstrated and 2-
iodobenzothiazole was synthesized beforehand. Lately, Abele et
al. reported the synthesis of certain fused imidazo[2,1-
b]benzothiazoles from o-dihaloarenes and 2-mercaptoimidazoles
using phase-transfer catalytic system (CuI/KOH/TBAB/phen).13
Although the transformation could construct the title
heterocycles, application of the method would be less attractive
due to the harsh conditions required therein (at 140-150 °C and
with KOH as the base), the low efficiency (generally in 7-59%
yields) and the narrow substrate scope.
Table 1. Optimization of the reaction conditionsa
Transition metal-catalyzed cross-coupling is one of the most
useful and efficient strategies in organic synthesis.9 Because of
their low-cost and convenience, Cu-mediated coupling reactions
have emerged as powerful tools for C-heteroatom bond
———
Entry
1
Cat.
CuI
L
Base
Sol.
Yield (%)b
85
L1
K2CO3
DMF
∗ Corresponding author. e-mail: lvxin@zjnu.cn.

2
Tetrahedron
2
CuI
L2
L3
L4
L5
L6
-
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
K3PO4
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
75
We began our domino synthesis with the reaction between o-
bromoiodobenzene 1a and 2-mercaptobenzimidazole 2a. To our
delight, a good yield of desired product 3a was isolated when the
reaction was initially promoted by CuI (10 mol%) and 1,10-
phenanthroline (phen, L1, 20 mol%) with K2CO3 (3 equiv) as
base in DMF at 120 °C (Table 1, entry 1). Different ligands were
screened (entries 1-6), and phen was identified as the best.
Notably, a moderate yield was obtained in a control experiment
without the addition of ligand (entry 7), indicating that
binucleophile 2a itself probably acted as a ligand. We also tested
other Cu catalysts such as CuBr, CuCl, Cu2O and Cu(OAc)2, and
CuI performed as the most efficient (compare entry 1 with entries
8-11). Hardly any desired product was detected when the reaction
was carried out without any catalyst (entry 12), showing that the
Cu catalyst is indispensable for the transformation. The yield
decreased when the catalyst loading was decreased to 5 mol%
(entry 13). While increasing the amount of the catalyst to 20
mol% did not lead to obvious improvement (entry 14). Various
bases were also tested (entries 1 and 15-17). Both K2CO3 and
Cs2CO3 were suitable, but K2CO3 was chosen as the preferred
base for its low cost. Further investigation found that reducing
the amount of K2CO3 to 2 equiv did not affect the result (entry
18). The effect of solvent was also studied, and DMF was the
optimal solvent (compare entry 18 with entries 19-22). Screening
on temperature showed that reacting at 120 °C was appropriate
for the process (compare entry 18 with entries 23 and 24).
3
CuI
65
4
CuI
40
5
CuI
73
6
CuI
78
7
CuI
64
8
CuBr
CuCl
Cu2O
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
78
9
70
10
83
11 Cu(OAc)2
60
12
13
14
15
16
17
18
-
trace
69c
85d
77
CuI
CuI
CuI
CuI
CuI
CuI
85
75
85e
19
20
21
22
23
24
CuI
CuI
CuI
CuI
CuI
CuI
L1
L1
L1
L1
L1
L1
K2CO3
K2CO3
K2CO3
DMAc
DMSO
NMP
75e
With the optimized conditions in hand, the generality and
scope of the domino reaction was evaluated by using various o-
dihaloarenes and 2-mercaptobenzimidazoles as the materials
(Table 2).15 Initially, we tested o-dihalobenzenes bearing
different leaving groups (X1, X2) (Table 1, entries 1-6). 1-Bromo-
2-iodobenzene acted as the most efficient (entry 1). 1-Chloro-2-
iodobenzene and o-diiodobenzene also performed well (entries 2-
3). Much lower yields were obtained when o-dibromobenzene
and 1-bromo-2-chlorobenzene were utilized (entries 4-5). Not
surprisingly, o-dichlorobenzene was ineffective for this domino
transformation (entry 6). A variety of 1-bromo-2-iodoarenes with
different substituents were then investigated (entries 7-16). In
most cases, good to excellent yields of the desired
benzimidazo[2,1-b]benzothiazoles were delivered within 24 h.
Either electron-donating or weak electron-withdrawing groups on
the dihalorides could be well tolerated (entries 7-13 and 15-16).16
However, the strong electron-withdrawing group on the o-
dihaloride gave a negative effect on the reaction and a moderate
yield was obtained (entry 14).16 Notably, heteroaromatic
substrate such as 3-bromo-2-iodopyridine 1o was also proved
applicable, giving the desired benzo[4’,5’]imidazo[2’,1’:2,3]-
thiazolo[5,4-b]pyridine 3j in 92% yield (entry 15). Pentacyclic
benzimidazo[2,1-b]benzothiazole 3k was selectively assembled
in an excellent yield from 1-bromo-2-iodonaphthalene 1p (entry
16). A low yield was isolated when dibromoalkene 1q was tested,
probably due to the special activity of the dibromoalkene and/or
the instability of the product in these conditions (entry 17). We
also investigated the domino reactions with substituted 2-
mercaptobenzimidazoles (Table 2, entries 18-21). Both electron-
donating and electron-withdrawing substituents (Me, MeO, Cl,
and NO2) on the phenyl ring of the binuclephiles were also
compatible with the conditions. 5-Nitro-1H-benzo[d]imidazole-
2-thiol (2e) afforded a relatively lower yield, maybe because of
its weaker nucleophilicity (entry 21). As expected, in these cases,
the substituted 2-mercaptobenzimidazole gave a mixture of two
regioisomers, due to the two different tautomerization directions
of the binuclephiles.
61e
78e
K2CO3 toluene
28e
K2CO3
K2CO3
DMF
DMF
75e , f
86e , g
a
Reaction conditions: 1-bromo-2-iodobenzene (1.05 mmol), 2-
mercaptobenzimidazole (1.0 mmol), Cu catalyst (0.1 mmol, 10
mol%), ligand (0.2 mmol, 20 mol%), base (3 equiv), in dry
solvent (3 mL), under N2, at 120 °C for 24 h.
b Isolated yield.
c CuI(0.05 mmol, 5 mol%) was used as the catalyst.
d CuI (0.15 mmol, 15 mol%) was used as the catalyst.
e K2CO3 (2 equiv) was used as the base.
f At 110 °C.
g At 130 °C.
In continuation of our ongoing efforts to assemble heterocycles
using domino transformations,14 and also to overcome the
inherent problems of the previously reported approaches to these
useful polycyclic molecules, herein we systematically
investigated the Cu-catalyzed domino synthesis of
benzimidazo[2,1-b]benzothiazoles from various o-dihaloarenes
and 2-mercaptobenzimidazoles.14 Comparing with the previous
protocols, our method conveniently delivers a wide variety of
benzimidazo[2,1-b]benzothiazole derivatives with higher
efficiency under milder conditions. Furthermore, a series of halo-
containing benzimidazo[2,1-b]benzothiazoles was selectively
prepared from multi-functional substrates, and further derivation
of the brominated ones was successfully achieved by Pd-
catalyzed Suzuki coupling. In addition, the effect of ligand was
also carefully investigated to further enhance the efficiency.
As shown in Scheme 1, the utility of the present method is
demonstrated by the scale-up experiment, where running the

3
reaction between 1a and 2a on 10 mmol scale in a simple two-
necked flask delivered the desired product 3a in good yield.
Table 2. Cu-catalyzed one-pot synthesis of benzimidazo[2,1-b]benzothiazoles.
Entry
1
Substrate 1
Nucleophile 2
Product 3
Time (h)
24
Yield (%)b
85
2a
1a
3a
2
3
28
18
80
78
2a
2a
2a
2a
2a
2a
3a
3a
3a
3a
3a
1b
1c
1d
1e
1f
4
5
36
40
48
24
45
25
6
trace
82
7
8
1g
3b
24
78
2a
1h
3c
24
24
87
77
9
2a
2a
1i
1j
3d
10
3e
24
24
24
25
74
73
70
56
11
12
2a
2a
1k
3f
1l
3g
13
14
2a
2a
1m
1n
3h
3i
65c
92
18
18
15
16
2a
2a
1o
3j
Br
I
95
1p
3k
3l
24
24
28
17
18
2a
2b
1q
42d
68
(51:49)e
1a
3m + 3m’

4
Tetrahedron
74
(63:37)e
19
20
21
24
24
36
1a
1a
1a
2c
3n + 3n’
3o + 3o’
3p + 3p’
72
(67:33)e
2d
2e
57
(80:20)e
a Reaction conditions: substrate 1 (1.05 mmol), 2-mercaptobenzimidazole 2 (1.0 mmol), CuI (0.1 mmol, 10 mol%), phen (0.2 mmol, 20
mol%) and K2CO3 (2 equiv) in DMF (3 mL) under N2 at 120 °C.
b Isolated yield.
c 2,9-Dimethyl-1,10-phenanthroline (neocuproine) was utilized as the ligand instead of phen.
d 2,2’-Bipyridyl (bipy) was utilized as the ligand instead of phen.
e A mixture of two isomers was obtained (the isomeric ratio in parenthesis was approximately determined by 1H NMR).
additional handle for further derivation of the products. As shown
in Table 3, a variety of tri-functionalized substrates 1s-1y were
utilized to react with 2a, and the desired halo-containing
benzimidazo[2,1-b]benzothiazoles were exclusively obtained in
Scheme 1. Scale-up experiment for the synthesis of product 3a
moderate to excellent yields. It is noticeable that 1,2-dibromo-3-
iodobenzene 1s presents the highest reactivity and gave 94%
yield of the brominated product (Table 3, entry 2). While 1-
bromo-2-iodo-3-nitrobenzenes were relatively less reactive and
afforded the products in moderate yields (entries 7 and 8).
Further studies showed that a range of functional substituents
such as Cl, Br and NO2 on the o-dihaloarenes were also
compatible under our conditions, which might provide an
Table 3. Cu-catalyzed selective one-pot synthesis of halo-containing benzimidazo[2,1-b]benzothiazolesa
Entry
1
R2
Product 3
Time (h)
22
Yield (%) b
70
1r
3q
3r
3s
2
3
4
18
30
36
30
94
68
61
1s
1t
1u
1v
3t
3f
5
6
69
35
30
76
53
1w
1x
3u
3s
7
c
54

5
36
41
8
c
49
1y
3t
Reaction conditions: substrate 1 (1.05 mmol), 2-mercaptobenzimidazole 2a (1.0 mmol), CuI (0.1 mmol, 10 mol%), phen (0.2 mmol,
a
20 mol%), and K2CO3 (2 mmol, 2 equiv) in DMF (3 mL) under N2 at 120 oC.
b Isolated yield.
c Neocuproine was utilized as the ligand instead of phen.
To further probe the ligand effect on these cascade reactions,
structurally modified phenanthroline ligands (L7-L9) were also
examined for the reaction between 1a and 2a (Scheme 2). And it
was found that neocuproine (L7) showed slightly better than
phen (L1), whereas 4,7-diphenyl-1,10-phenanthroline (L8) and
4,7-dimethoxyl 1,10-phenanthroline (L9) were inferior to L1.
entries under the promotion of phen (Table 2, entries 14, 17 and
21; Table 3, entries 7 and 8) were also investigated (Scheme 3).
Scheme 3. Further investigation on the effect of other ligands
As shown in Scheme 3, for the reactions of electron-poor
substrates 1 (1n, 1x and 1y) with 2a, neocuproine (L7) was the
most efficient ligand (phen also acted as a good candidate for
these reactions). However, phen appeared to be the optimal
promoter for the reaction with electron-deficient binucleophile 5-
Scheme 2. The effect of phenanthroline ligand
Considering that other types of ligands such as 2,2’-bipyrridyl
(Bipy, L2), N,N-dimethylglycine (DMG, L5) and pipecolinic
acid (L6) afforded comparable level of efficiency (Table 1), the
effects of these ligands (including L7) for the unsatisfactory
nitro-1H-benzo[d]imidazole-2-thiol (2e). And the domino
reactions of 1q indicated that bipy L2 was the best ligand when
dibromoalkene was utilized as the substrate.
Table 4. Pd-catalyzed reactions of bromo-containing benzimidazo[2,1-b]benzothiazoles with arylboronic acidsa
Entry
1
Compound 3
Reagent 4
Product 5
Time (h)
15
Yield (%) b
72
4a
3r
5a
2
3
4b
10
10
18
83
85
82
3q
5b
3q
3q
4c
5c
4
4d
5d

6
Tetrahedron
5
6
3q
3q
12
10
79
80
4e
4a
5e
5f
7
3q
15
88
4f
5g
Reaction conditions: benzo[d]benzo[4,5]imidazo[2,1-b]thiazole (0.3 mmol, 1 equiv), arylboronic acid (0.45 mmol, 1.5 equiv),
a
Pd(PPh3)4 (0.1 mmol, 10 mol%), and K2CO3 (0.45 mmol, 1.5 equiv) in dioxane/H2O (6 mL, 5:1, v:v) under N2 at 100 °C.
b Isolated yield.
S.; Marinelli, L.; Novellino, E.; Chiarini, A. J. Med. Chem. 2008,
51, 1592-1600.
The derivation of the halo benzimidazo[2,1-b]benzothiazoles
is also feasible. We found that under proper Pd catalysis, several
bromo-containing products could smoothly react with
arylboronic acids to afford the corresponding arylated
benzimidazo[2,1- b]benzothiazole derivatives (Table 4, entries 1-
7).17 As a novel class of imidazo[2,1-b]benzothiazole derivatives,
these polycyclic molecules possess unprecedented structural
features and might be of particular biological interest.
5. Several imidazo[2,1-b]benzothiazoles have been reported as
potential drugs with antineuropathic, antimicrobial, and anticancer
activities. For examples, see: (a) Yousefi, B. H.; Manook, A.;
Drzezga, A.; Reutern, B.; Schwaiger, M.; Wester, H. J.;
Henriksen, G. J. Med. Chem. 2011, 54, 949-956. (b) Malik, J. K.;
Noolvi, M. N.; Manvi, F. V.; Nanjwade, B. K.; Patel, H. M.;
Manjula, S. N.; Rao, C. M.; Barve, A. Lett. Drug Des. Discov.
2011, 8, 717-724. (c) Al-Tel, T. H.; Al-Qawasmeh, R. A.;
Zaarour, R. Eur. J. Org. Chem. 2011, 46, 1874-1881. (d) Palkar,
M.; Noolvi, M.; Sankangoud, R.; Maddi, V.; Gadad, A.; Nargund,
L. V. G. Arch. Pharm. 2010, 343, 353-359.
In summary, we have described an efficient and convenient
approach to benzimidazo[2,1-b]benzothiazoles through Cu-
catalyzed domino reactions. A variety of o-dihaloarenes and 2-
mercaptobenzimidazoles with electron-donating and electron-
withdrawing substituents smoothly gave the desired products.
Moreover, tri-functionalized substrates selectively delivered the
halo-containing benzimidazo[2,1-b]benzothiazoles, and the
brominated ones successfully reacted with arylboronic acids
under Pd catalysis to give the corresponding aryl
6. Lin, D. C. K.; DeJongh, D. C. J. Org. Chem. 1974, 39, 1780-1782.
7. D’Amico, J. J.; Tung, C. C.; Dahl, W. E. J. Org. Chem. 1977, 42,
600-602.
8. Zhang, X. H.; Jia, J.; Ma, C. Org. Biomol. Chem. 2012, 10, 7944-
7948.
9. For selected reviews, see: (a) Beletskaya, I. P.; Ananikov, V. P.
Chem. Rev. 2011, 111, 1596-1636. (b) Carril, M.; SanMartin, R.;
Dominguez, E. Chem. Soc. Rev. 2008, 37, 639-647. (c) de
Meijere, A., Diederich, F., Eds. Metal-Catalyzed Cross-Coupling
Reactions, 2nd. Wiley-VCH: Weinheim, Germany, 2004.
10. For selected recent reviews, see: (a) Surry, D. S.; Buchwald, S. L.
Chem. Sci. 2010, 1, 13-31. (b) Monnier, F.; Taillefer, M. Angew.
Chem. Int. Ed. 2009, 48, 6954-6971. (c) Ma, D. W.; Cai, Q. Acc.
Chem. Res. 2008, 41, 1450-1460. (d) Evano, G.; Blanchard, N.;
Toumi, M. Chem. Rev. 2008, 108, 3054-3131.
benzo[d]benzo[4,5]imidazo[2,1-b]thiazole
derivatives.
The
methodology may be practical and useful for the synthesis of
related heterocyclic compounds of biological and medicinal
interests.
Acknowledgments
11. For reviews, see: (a) Liu, Y.; Wan, J. –P. Chem. Asian J. 2012, 7,
1488-1501. (b) Liu, Y.; Wan, J. –P. Org. Biomol. Chem. 2011, 9,
6873-6894.
This work was financially supported by the National Natural
Science Foundation of China (No. 21202152) and the Zhejiang
Provincial Natural Science Foundation (No. Y4110044).
12. Wu, Z. Q.; Huang, Q.; Zhou, X. G.; Yu, L. T.; Li, Z. K.; Wu, D.
Eur. J. Org. Chem. 2011, 5242-5245.
13. During the preparation of this manuscript, Abele et al. reported the
synthesis of the fused imidazo[2,1-b]benzothiazoles from o-
dihaloarenes and 2-mercaptoimidazoles using phase-transfer
catalytic system: (a) Abele, E.; Beresneva, T. Heterocycl. Lett.
2013, 3, 397-401. (b) Beresneva, T.; Abele, E. Chem. Heterocycl.
Comp. 2013, 49, 345-347.
References and notes
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Granaiola, M.; Leoni, A.; Locatelli, A.; Morigi, R.; Rambaldi, M.;
Varoli, L.; Calonghi, N.; Cappadone, C.; Farruggia, G.; Zini, M.;
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14. (a) Yuan, G.; Liu, H.; Gao, J.; Yang, K.; Niu, Q.; Mao, H.; Wang,
X.; Lv, X.; J. Org. Chem. 2014, 79, 1749-1757. (b) Niu, Q.; Mao,
H.; Yuan, G.; Gao, J.; Liu, H.; Tu, Y.; Wang, X.; Lv, X. Adv.
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J.; Ma, Z.; Jiang, Z.; Wang, X.; Lv, X. Org. Biomol. Chem. 2012,
10, 1602-1611.
15. General procedure for Cu-catalyzed one-pot synthesis of
benzimidazo[2,1-b]benzothiazoles. An oven-dried Schlenk tube
was charged with a magnetic stir bar, binucleophile 2-
mercaptobenzimidazole 2 (1.0 mmol, 1.0 equiv), CuI (0.1 mmol,
10 mol %), phen (0.2 mmol, 20 mol %), and K2CO3 (2.0 mmol, 2
equiv). The tube was capped and then evacuated and backfilled
with nitrogen (3 times). Under a positive pressure of nitrogen, a
solution of o-dihaloarene 1 (1.05 mmol, 1.05 equiv) in DMF (3
mL) was added via syringe. The tube was sealed and allowed to
stir at 120 °C (monitored by TLC). After being cooled to room
temperature, EtOAc (40 mL) was added and the mixture was
washed with brine (20 mL × 3). The organic phase was dried over
Na2SO4 and concentrated. The residue was purified by column
2. Vu, C. B.; Bemis, J. E.; Disch, J. S.; Ng, P. Y.; Nunes, J. J.; Milne,
J. C.; Carney, D. P.; Lynch, A. V.; Smith, J. J.; Lavu, S.; Lambert,
P. D.; Gagne, D. J.; Jirousek, M. R.; Schenk, S.; Olefsky, J. M.;
Perni, R. B. J. Med. Chem. 2009, 52, 1275-1283.
3. Moraski, G. C.; Markley, L. D.; Chang, M.; Cho, S.; Franzblau, S.
G.; Hwang, C. H.; Boshoff, H.; Miller, M. J. Boorg. Med. Chem.
2012, 20, 2214-2220.
4. (a) Locatelli, A.; Cosconati, S.; Micucci, M.; Leoni, A.; Marinelli,
L.; Bedini, A.; Loan, P.; Spampinato, S. M.; Novellino, E.;
Chiarini, A.; Budriesi, R. J. Med. Chem. 2013, 56, 3866-3877. (b)
Budriesi, R.; Ioan, P.; Locatelli, A.; Cosconati, S.; Leoni, A.;
Ugenti, M. P.; Andreani, A.; Toro, R. D.; Bedini, A.; Spampinato,

7
chromatography on silica gel using petrol/EtOAc (10:1 → 3:1,
v:v) as eluent to give product 3.
mmol, 10 mol %), and K2CO3 (0.45 mmol, 1.5 equiv). The tube
was capped and then evacuated and backfilled with nitrogen (3
16. The phenomenon is different from Ma’s report, indicating that the
present reaction may undergo a different pathway instead of the
SNAr process.
17. General procedure for Pd-catalyzed coupling of brominated
benzimidazo[2,1-b]benzothiazoles with benzoboric acids. An
oven-dried Schlenk tube was charged with a magnetic stir bar,
brominated benzimidazo[2,1-b]benzothiazole 3 (0.3 mmol, 1
equiv), arylboronic acid 4 (0.45 mmol, 1.5 equiv), Pd(PPh3)4 (0.03
times). Under a positive pressure of nitrogen, H2O (1 mL) and 1,4-
dioxane (5 mL) was then added subsequently. The tube was sealed
and allowed to stir at 100 °C (monitored by TLC). After being
cooled to room temperature, CH2Cl2 (20 mL) was added and the
mixture was washed with brine (10 mL × 3). The organic phase
was dried over Na2SO4 and concentrated. The residue was purified
by column chromatography on silica gel using petrol/EtOAc (15:1
→ 8:1, v:v) as eluent to give product 5.

8
Tetrahedron

9

10
Tetrahedron

11
Table 1. Optimization of the reaction conditionsa
Entry
Cat.
CuI
L
Base
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
K3PO4
K2CO3
Sol.
Yield (%)b
85
1
2
3
4
5
6
7
8
9
10
L1
L2
L3
L4
L5
L6
-
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CuI
75
CuI
65
CuI
40
CuI
73
CuI
78
CuI
64
CuBr
CuCl
Cu2O
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
78
70
83
11 Cu(OAc)2
60
12
13
14
15
16
17
18
-
trace
69c
85d
77
CuI
CuI
CuI
CuI
CuI
CuI
85
75
85e
19
20
21
22
23
24
CuI
CuI
CuI
CuI
CuI
CuI
L1
L1
L1
L1
L1
L1
K2CO3
K2CO3
K2CO3
DMAc
DMSO
NMP
75e
61e
78e
K2CO3 toluene
28e
K2CO3
DMF
75e , f
86e , g
K2CO3
DMF
a Reaction conditions: 1-bromo-2-iodobenzene (1.05 mmol), 2-mercaptobenzimidazole (1.0 mmol), Cu catalyst (0.1 mmol, 10 mol%),
ligand (0.2 mmol, 20 mol%), base (3 equiv), in dry solvent (3 mL), under N2, at 120 °C for 24 h.
b Isolated yield.
c CuI(0.05 mmol, 5 mol%) was used as the catalyst.
d CuI (0.15 mmol, 15 mol%) was used as the catalyst.
e K2CO3 (2 equiv) was used as the base.
f At 110 °C.
g At 130 °C.

12
Tetrahedron
Table 2. Cu-catalyzed one-pot synthesis of benzimidazo[2,1-b]benzothiazoles.
Entry
1
Substrate 1
Nucleophile 2
Product 3
Time (h)
24
Yield (%)b
85
2a
1a
3a
2
3
28
18
36
40
48
24
80
78
2a
2a
2a
2a
2a
2a
3a
3a
3a
3a
3a
1b
1c
1d
1e
1f
4
5
45
25
6
trace
82
7
8
1g
3b
24
78
2a
1h
3c
24
24
87
77
9
2a
2a
1i
1j
3d
10
3e
24
24
24
25
74
73
70
56
11
12
2a
2a
1k
3f
1l
3g
13
14
2a
2a
1m
1n
3h
3i
65c
92
18
18
15
16
2a
2a
1o
3j
Br
I
95
1p
3k
3l
24
24
24
28
17
18
2a
1q
42d
68
(51:49)e
1a
1a
2b
2c
3m + 3m’
74
(63:37)e
19

13
3n + 3n’
3o + 3o’
3p + 3p’
72
(67:33)e
20
21
24
36
1a
1a
2d
2e
57
(80:20)e
a Reaction conditions: substrate 1 (1.05 mmol), 2-mercaptobenzimidazole 2 (1.0 mmol), CuI (0.1 mmol, 10 mol%), phen (0.2 mmol, 20
mol%) and K2CO3 (2 equiv) in DMF (3 mL) under N2 at 120 °C.
b Isolated yield.
c 2,9-Dimethyl-1,10-phenanthroline (neocuproine) was utilized as the ligand instead of phen.
d 2,2’-Bipyridyl (bipy) was utilized as the ligand instead of phen.
e A mixture of two isomers was obtained (the isomeric ratio in parenthesis was approximately determined by 1H NMR).

14
Tetrahedron
Table 3. Cu-catalyzed selective one-pot synthesis of halo-containing benzimidazo[2,1-b]benzothiazolesa
Entry
1
R2
Product 3
Time (h)
22
Yield (%) b
70
1r
3q
3r
3s
2
3
4
18
30
36
30
94
68
61
1s
1t
1u
1v
3t
3f
5
6
69
35
30
76
53
1w
3u
3s
7
8
c
1x
1y
54
36
41
c
49
3t
a
Reaction conditions: substrate 1 (1.05 mmol), 2-mercaptobenzimidazole 2a (1.0 mmol), CuI (0.1 mmol, 10 mol%), phen (0.2 mmol,
20 mol%), and K2CO3 (2 mmol, 2 equiv) in DMF (3 mL) under N2 at 120 oC.
b Isolated yield.
c Neocuproine was utilized as the ligand instead of phen.

15
Table 4. Pd-catalyzed reactions of bromo-containing benzimidazo[2,1-b]benzothiazoles with arylboronic acidsa
Entry
1
Compound 3
Reagent 4
Product 5
Time (h)
15
Yield (%) b
72
4a
3r
5a
2
3
4b
10
10
83
85
3q
5b
3q
4c
5c
4
5
3q
3q
18
12
82
79
4d
5d
4e
4a
5e
6
7
3q
3q
10
15
80
88
5f
4f
5g
a
Reaction conditions: benzo[d]benzo[4,5]imidazo[2,1-b]thiazole (0.3 mmol, 1 equiv), arylboronic acid (0.45 mmol, 1.5 equiv),
Pd(PPh3)4 (0.1 mmol, 10 mol%), and K2CO3 (0.45 mmol, 1.5 equiv) in dioxane/H2O (6 mL, 5:1, v:v) under N2 at 100 °C.
b Isolated yield.

16
Tetrahedron
Graphical Abstract
Synthesis of benzimidazo[2,1-b]benzothiazole derivatives through sequential Cu-catalyzed domino
coupling and Pd-catalyzed Suzuki reaction
Jilong Gao, Jiaoyan Zhu, Lubin Chen, Yingying Shao, Jiaqi Zhu, Yijia Huang, Xiaoxia Wang and Xin Lv∗
Zhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004,
People’s Republic of China
———
∗ Corresponding author. e-mail: lvxin@zjnu.cn