Copper- and Palladium-Catalyzed Cross-Coupling Reactions for the Synthesis of N-Fused Benzo[4,5]imidazo[2,1-b]thiazole Derivatives via Substituted trans-1,2-Diiodoalkenes, 1H-Benzo[d]imidazole-2-thiols, and Halobenzenes

Article abstract of DOI:10.1021/acs.joc.7b00162

Two transition metal (Cu and Pd)-catalyzed C-S, C-N, and C-C bond cross-coupling reactions for the preparation of N-fused benzo[4,5]imidazo[2,1-b]thiazole derivatives were developed. A variety of 3-substituted and 2,3-disubstituted benzo[4,5]imidazo[2,1-b]thiazoles were efficiently and conveniently synthesized from the coupling reaction via trans-1,2-diiodoalkenes, 1H-benzo[d]imidazole-2-thiols, and halobenzenes in moderate to excellent yields.

Full text of DOI:10.1021/acs.joc.7b00162

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Article
Copper and Palladium Catalyzed Cross-Coupling Reactions for the Synthesis
of N-Fused Benzo[4,5]imidazo[2,1-b]thiazole Derivatives via Substituted
trans-1,2-Diiodoalkenes, 1H-Benzo[d]imidazole-2-thiols and Halobenzenes
Guodong Shen, Bingchuan Yang, Xianqiang Huang, Yaxin Hou,
Huan Gao, Jichun Cui, Chuansheng Cui, and Tongxin Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00162 • Publication Date (Web): 16 Mar 2017
Downloaded from http://pubs.acs.org on March 16, 2017
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Copper and Palladium Catalyzed Cross-Coupling Reactions for the Synthesis
of N-Fused Benzo[4,5]imidazo[2,1-b]thiazole Derivatives via Substituted trans-
1,2-Diiodoalkenes, 1H-Benzo[d]imidazole-2-thiols and Halobenzenes
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Guodong Shen,* Bingchuan Yang, Xianqiang Huang, Yaxin Hou, Huan Gao, Jichun Cui, Chuansheng Cui and
Tongxin Zhang*
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School of Chemistry and Chemical Engineering, School of Pharmacy, Liaocheng University, Liaocheng
252000, Shandong, PR China
Tel & Fax: (+)86ꢀ635ꢀ8239680; eꢀmail: shenguodong33@163.com, xintongzhang123@163.com.
TOC Graphic
R3
S
I
H
S
X
CuI
N
N
N
H
Pd(OAc)2/PPh3
R1
N
1,10-phenanthroline
R2
N
SH
R1
R1
K2CO3, DMF
100 oC, N2
I
N
H
Cs2CO3, p-xylene
135 oC, N2
R3
R2
27 examples
R2
d
a
b
c
f
R1=Ar, Bn, n-Bu, Cyclopropyl
R2=H, CH3, Cl, F .
R3=H, CH3, Cl
18 examples
up to 96% yields
up to 82% yields
X=Br, I
Abstract
Two transition metal (Cu and Pd) catalyzed CꢀS, CꢀN and CꢀC bonds crossꢀcoupling reactions
for the preparation of Nꢀfused benzo[4,5]imidazo[2,1ꢀb]thiazole derivatives were developed. A
variety of 3ꢀsubstituted and 2,3ꢀdisubstituted benzo[4,5]imidazo[2,1ꢀb]thiazoles were efficiently
and conveniently synthesized from the coupling reaction via transꢀ1,2ꢀdiiodoalkenes, 1Hꢀ
benzo[d]imidazoleꢀ2ꢀthiols and halobenzenes in moderate to excellent yields.
Introduction
Imidazol[2,1ꢀb]ꢀthiazole derivatives are important class of molecules for their biological and
pharmaceutical activities, such as calcium channel antagonistic activity,1 antifungal properties,2
antiꢀinflammatory properties,3 antitumor agent,4 antidiabetic agent,5 antitubercular agent,6 antiꢀ
cardiovascular agent7 and so on.8 Although imidazol[2,1ꢀb]ꢀthiazole derivatives play important
roles in medicinal chemistry, efficient synthetic routes are rare. The classical method for these Nꢀ
fused heterocycles involves the reaction of 2ꢀmercaptobenzoimidazole with αꢀbromoꢀ
acetophenones9 and the photochemical recombination of 1ꢀ(2ꢀbenzothiazolyl)ꢀbenzotriazole.10
However, these methods have some shortcomings and limitations, such as requiring strong acid
and special starting materials, tedious procedures, and suffering from the low efficiency and
narrow scopes.
Transition metalꢀcatalyzed crossꢀcoupling reactions are of paramount importance in organic
synthesis.11 In the past decades, copper and palladium catalyzed CꢀX (X=C, N, O, S, etc.) bond
formation reactions have drawn considerable attention for their convenience and efficiency.12
These reactions have been successfully applied in the preparation of pharmaceuticals,
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agrochemicals and advanced materials on both laboratory and industrialscales. In 2010, Chen et
al. reported a copperꢀcatalyzed method for the synthesis of imidazol[2,1ꢀb]ꢀthiazole derivatives
through regioselective 1,2ꢀaminothiolation of 1,1ꢀdibromoalkenes.13 In 2011, Wu et al. reported
another copperꢀcatalyzed reaction of 2ꢀiodoaniline and 2ꢀiodobenzothiazole to give
benzimidazo[2,1ꢀb]benzothiazole derivatives.14 In 2012, Li et al. found a novel method for the
preparation of Nꢀfused heterocycles via a CspꢀS coupling reaction and a sequence of 5ꢀendoꢀdig
cyclization.15 Lately, Abele et al. reported the synthesis of certain fused imidazo[2,1ꢀ
b]benzothiazoles from oꢀdihaloarenes and 2ꢀmercaptoimidazoles using phaseꢀtransfer catalytic
system.16 Recently, Lv et al. synthesized a variety of benzo[d]benzo[4,5]imidazo[2,1ꢀb]thiazoles
by the copperꢀcatalyzed domino coupling of oꢀdihaloarenes with 2ꢀmercaptobenzimidazoles.17 In
continuation of our ongoing efforts to assemble heterocycles,18 we report two efficient copper
and palladiumꢀcatalyzed crossꢀcoupling reactions for the synthesis of benzo[4,5]imidazo[2,1ꢀ
b]thiazole derivatives via substituted transꢀ1,2ꢀdiiodoalkenes, 1Hꢀbenzo[d]imidazoleꢀ2ꢀthiols
and halobenzenes. Our designed and proposed approach was summarized in Figure 1.
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Figure 1. Designed synthesis of benzo[4,5]imidazo[2,1-b]thiazole derivatives.
Results and Discussion
Initially, (E)ꢀ(1,2ꢀdiiodovinyl)benzene 1a and 1Hꢀbenzo[d]imidazoleꢀ2ꢀthiol 1b were selected
as the model substrates to identify and optimize the reaction parameters including transition
metal catalysts, reaction temperature, base and solvent. When the reaction was carried out with
CuI (0.075 mmol)/N, Nꢀdimethylglycine (0.15 mmol), (E)ꢀ(1,2ꢀdiiodovinyl)benzene 1a (0.5
mmol), 1Hꢀbenzo[d]imidazoleꢀ2ꢀthiol 1b (0.5 mmol) and K2CO3 (1.0 mmol) in DMF (2.0 mL)
under N2 atmosphere for 24 h, the desired product 3ꢀphenylbenzo[4,5]imidazo[2,1ꢀb]thiazole 1c
could be isolated in 28% yield (Table 1, entry 1). N, N’ꢀDimethylethaneꢀ1,2ꢀdiamine (DMEDA)
or 1,10ꢀphenanthroline (1,10ꢀPhen) was tested as the ligand under the reaction condition, and
1,10ꢀphenanthroline provided better yield (Table 1, entries 2ꢀ3). The reaction was investigated in
other solvents (toluene, MeCN, dioxane and DMSO) and DMF was found to be the best choice
(Table 1, entries 3ꢀ7). During the study of bases, Cs2CO3 also showed good efficiency (Table 1,
entries 8ꢀ9). The solvents such as toluene, MeCN, dioxane and DMSO were also investigated in
the presence of Cs2CO3, but the product yields were not good (Table 1, entries 10ꢀ13). From the
experiment we can see K2CO3 showed the best efficiency. However, the reaction at lower (90oC)
o
or higher (110 C) temperatures evidently decreased the reaction yields (Table 1, entries 14ꢀ15).
Other copper salts such as CuCl and CuBr were also investigated and CuI provided the best yield
(Table 1, entries 16ꢀ17). Without the ligand or the base, the product was obtained in low yield
(Table 1, entries 18ꢀ19). From the above experiments we can conclude that the entry 3 shows the
best reaction conditions.
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Table 1. Optimization of the reaction conditions.a
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T
Yield
(%)b
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Entry
1
Catalyst
Solvent
DMF
Base
(oC)
CuI/N,Nꢀ
K2CO3
100
28
dimethylglycine
CuI/DMEDA
CuI/1,10ꢀPhen
CuI/1,10ꢀPhen
CuI/1,10ꢀPhen
CuI/1,10ꢀPhen
CuI/1,10ꢀPhen
CuI/1,10ꢀPhen
CuI/1,10ꢀPhen
CuI/1,10ꢀPhen
CuI/1,10ꢀPhen
CuI/1,10ꢀPhen
CuI/1,10ꢀPhen
CuI/1,10ꢀPhen
CuI/1,10ꢀPhen
CuBr/1,10ꢀPhen
CuCl/1,10ꢀPhen
CuI
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
DMF
DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
100
100
100
100
100
100
41
81
20
45
36
44
80
61
31
40
64
15
65
70
73
62
22
18
toluene
MeCN
dioxane
DMSO
DMF
Cs2CO3 100
KOAc 100
Cs2CO3 100
Cs2CO3 100
Cs2CO3 100
Cs2CO3 100
DMF
toluene
MeCN
dioxane
DMSO
DMF
DMF
DMF
DMF
DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
/
90
110
100
100
100
100
CuI/1,10ꢀPhen
DMF
aReaction conditions: copper salt (0.075 mmol), ligand (0.15 mmol), (E)ꢀ(1,2ꢀdiiodovinyl)benzene 1a (0.5
mmol), 1Hꢀbenzo[d]imidazoleꢀ2ꢀthiol 1b (0.5 mmol) and base (1.0 mmol) in solvent (2.0 mL) under N2
atmosphere for 24 h. bIsolated yield after flash chromatography based on 1a.
Table 2 Scope of the copper catalyzed cross-coupling reaction for the synthesis of 3-
substituted benzo[4,5]imidazo[2,1-b]thiazoles.a
Entry
1
Yield (%)b
82
a
b
c
1a
2a
3a
1b
1b
1c
2c
2
3
80
78
1b
1b
3c
4
80
4a
4c
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83
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1b
5a
5c
1b
6a
6c
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1b
7a
7c
8
71
1b
8a
8c
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72
78
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73
66
1b
9a
10a
11a
9c
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1b
1b
1b
1b
10c
11c
12a
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12c
13c
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83(1:1.2)c
75(1:1) c
1a
1a
4a
4a
6a
6a
2b
14c+15c
3b
2b
16c+17c
18c+19c
20c+21c
22c+23c
83(1:1.2)c
73(1:1.2)c
75(1:1.2)
70(1:1.2)
3b
2b
3b
24c+25c
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4a
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26c
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27c
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aReaction conditions: CuI (0.075 mmol), 1,10ꢀPhen (0.15 mmol), transꢀ1,2ꢀdiiodoalkenes a (0.5 mmol), 1Hꢀ
benzo[d]imidazoleꢀ2ꢀthiols b (0.5 mmol) and K2CO3 (1.0 mmol) in DMF (2.0 mL) under N2 atmosphere for 24
b
c
h. Isolated yields after flash chromatography based on a. A mixture of two isomers was obtained (the
isomeric ratio was approximately determined by 1H NMR).
With the optimized reaction conditions in hand, the scope of substrates was further
investigated (Table 2). From the experimental results we could conclude that the reaction yields
were influenced by electronic effects. The substrates of transꢀ1,2ꢀdiiodoalkenes a with electronꢀ
donating groups (CH3, nꢀBu and tꢀBu) and electronꢀwithdrawing groups (F, Cl and Br) generated
the desired products in moderate to good yields (Table 2, entries 2ꢀ9). The yields of substrates a
bearing electronꢀdonating groups were better than substrates a bearing electronꢀwithdrawing
groups. When (E)ꢀ1,2ꢀdiiodohexꢀ1ꢀene 10a, (E)ꢀ(2,3ꢀdiiodoallyl)benzene 11a and (E)ꢀ(1,2ꢀ
diiodovinyl)cyclopropane 12a were used, the desired products were got in moderate yields
(Table 2, entries 10ꢀ12). (E)ꢀ3ꢀ(1,2ꢀDiiodovinyl)pyridine 13a could react with 1b and generate
the product 13c in 66% yield (Table 2, entry 13). The reactions of 1a with substituted 1Hꢀ
benzo[d]imidazoleꢀ2ꢀthiols b were also investigated (Table 2, entries 14ꢀ21). The yields were
also much lower when 1Hꢀbenzo[d]imidazoleꢀ2ꢀthiols b bearing electronꢀwithdrawing groups
(Table 2, entries 14ꢀ16). When monoꢀsubstituted1Hꢀbenzo[d]imidazoleꢀ2ꢀthiols b were used to
proceed the reaction, the mixtures of two isomers were obtained, the isomeric ratio were
1
approximately determined by H NMR (Table 2, entries 14ꢀ15, 17ꢀ20). 5, 6ꢀDifluoroꢀ1Hꢀ
benzo[d]imidazoleꢀ2ꢀthiol 4b reacted with a and gave the corresponding products in moderate
yields (Table 2, entries 20ꢀ21).
Table 3. Optimization of the reaction conditions.a
T
Yield
(%)b
45
46
51
21
35
96
96
90
31
13
47
Entry
Catalyst
Solvent
Base
(oC)
1
2
3
4
5
6
7
8
9
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
PdCl2/PPh3
DMA
DMA
DMF
DMSO
dioxane
pꢀxylene
pꢀxylene
pꢀxylene
pꢀxylene
Cs2CO3 145
Cs2CO3 150
Cs2CO3 145
Cs2CO3 145
Cs2CO3 145
Cs2CO3 145
Cs2CO3 135
Cs2CO3 130
Cs2CO3 135
Cs2CO3 135
Cs2CO3 135
10
11
12
Pd(dppf)Cl2/PPh3 pꢀxylene
Pd(OAc)2
Pd(OAc)2/PPh3
pꢀxylene
pꢀxylene
/
135
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aReaction conditions: Pd salt (0.015 mmol), ligand (0.03 mmol), 3ꢀphenylbenzo[4,5]imidazo[2,1ꢀb]thiazole 1c
(0.3 mmol), iodobenzene 1f (0.40 mmol) and base (0.6 mmol) in solvent (1.5 mL) under N2 atmosphere for 24
h. bIsolated yield after flash chromatography based on 1c.
6
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8
9
With the 3ꢀsubstituted benzo[4,5]imidazo[2,1ꢀb]thiazoles c in hand, we tried to synthesize a
new series of 2,3ꢀdisubstituted benzo[4,5]imidazo[2,1ꢀb]thiazolesderivatives d by the palladiumꢀ
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catalyzed crossꢀcoupling reactions of
c
with halobenzenes f. Firstly, 3ꢀ
phenylbenzo[4,5]imidazo[2,1ꢀb]thiazole 1c and iodobenzene 1f were selected as the model
substrates to identify and optimize the reaction parameters. When the reaction was carried out
with Pd(OAc)2 (0.015 mmol)/PPh3 (0.03 mmol), benzo[4,5]imidazo[2,1ꢀb]thiazoles c (0.3 mmol),
iodobenzene 1f (0.40 mmol) and Cs2CO3 (0.6 mmol) in DMA (1.5 mL) at 145 C under N2
atmosphere for 24 h, the desired product 2,3ꢀdiphenylbenzo[4,5]imidazo[2,1ꢀb]thiazole 1d could
be isolated in 45% yield (Table 3, entry 1). The structure of 1d was unambiguously elucidated by
Xꢀray crystallography (Figure 2). Raising the reaction temperature (150 C) did not improve the
yield of 1d (Table 3, entry 2). To our delight, when the reaction was investigated in other
solvents (DMF, DMSO, dioxane and pꢀxylene), pꢀxylene was found to be the best choice and 1d
o
o
o
was obtained in 96% yield (Table 3, entries 3ꢀ6). The screened reaction temperature (135 C)
provided the best yield (Table 3, entries 7ꢀ8). Other Pd source such as PdCl2 and Pd(dppf)Cl2
were also investigated and Pd(OAc)2 was the best choice (Table 3, entries 9ꢀ10). Without the
ligand or the base, the reaction yields decreased obviously (Table 3, entries 11ꢀ12). From the
above experiments we can conclude that the entry 7 shows the best reaction conditions.
Figure 2. X-ray crystallographic structure of 1d.
Then the scope of substrates was also investigated. The substrates of 3ꢀsubstituted
benzo[4,5]imidazo[2,1ꢀb]thiazoles c could react well with halobenzenes f, and generated the
corresponding products d in moderate to excellent yields (Table 4, 1d-16d). When the group R1
were aliphatic substituted or aromatic substituted groups, the yields were got in good to excellent
(Table 4, 1d-7d). The reaction yields were mainly influenced by the electronic effect of group R2.
The 3ꢀsubstituted benzo[4,5]imidazo[2,1ꢀb]thiazoles c bearing electronꢀdonating R2 groups
generated better yields than electronꢀwithdrawing R2 groups (Table 4, 8d-10d, 15-16d). The
substituted halobenzenes f were also tested and the products were got in excellent yield (Table 4,
11d-14d). A mixture of two isomers 20c and 21c was reacted with 1f to give a mixture of 15d
1
and 16d, and the isomeric ratio was approximately determined by H NMR (Table 4, 15d and
16d). When bromobenzene was used, the reactions could also proceed successfully (Table 4, 1dꢀ
2d). Through the methods (Condition A and Condition B) of Pdꢀcatalyzed crossꢀcoupling
reaction, two synthetic routes for 18d from 9c were developed (Figure 3).
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Table 4. Scope of the palladium catalyzed cross-coupling reaction for the synthesis of 2,3-
disubstituted benzo[4,5]imidazo[2,1-b]thiazoles.a,b
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9
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1d,96%(69%)c
5d, 93%
2d,90%(65%)c 3d, 95%
4d, 90%
8d, 78%
6d, 85%
7d, 80%
9d, 79%
10d, 75%
14d, 92%
11d, 90%
12d, 91%
13d, 90%
15d+16d, 94% (1:1.2)d
aReaction conditions: Pd(OAc)2 (0.015 mmol), PPh3 (0.03 mmol), 3ꢀsubstituted benzo[4,5]imidazo[2,1ꢀ
o
b]thiazoles c (0.3 mmol), halobenzenes f (0.4 mmol) and Cs2CO3 (0.6 mmol) in pꢀxylene (1.5 mL) at 135 C
under N2 atmosphere for 24 h. bIsolated yield after flash chromatography based on c. cBromobenzene was used.
dA mixture of 15d and 16d was obtained (the isomeric ratio was approximately determined by 1H NMR).
Figure 3. Two synthetic routes for the same benzo[4,5]imidazo[2,1-b]thiazole 18d.
o
Condition A: Pd(OAc)2/PPh3, Cs2CO3, pꢀxylene, N2, 24h, 135 C; Condition B: Pd(PPh3)4, 2M Na2CO3,
toluene, EtOH, N2, 24h, 100 oC.
Figure 4. Proposed mechanisms of the Cu and Pd catalyzed cross-coupling reactions.
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On the basis of the above results and previous work, two possible reaction mechanisms for the
Cu and Pd catalyzed crossꢀcoupling reactions were proposed in Figure 4. Firstly the intermediate
g was generated in the presence of CuI and base. Because of the steric hindrance of a, the
intermediate g could reacted with a to generate h via the selective oxidative addition reaction.
Then an reductive elimination reaction proceeded and h converted to intermediate e. Finally
intermediate e would proceed the same procedure of oxidative addition and reductive elimination
reaction to get the product c (Figure 4, eq 1). For the Pd catalyzed coupling reaction,
halobenzene f could convert to ArPdIIX in the presence of Pd(OAc)2 and PPh3, then ArPdIIX
could react with c to generate the intermediate i via the oxidative addition reaction, and reductive
elimination reaction would happen, leading to the product d (Figure 4, eq 2).
In summary, we have developed two Cu and Pd catalyzed CꢀS, CꢀN and CꢀC bonds crossꢀ
coupling reactions for the preparation of benzo[4,5]imidazo[2,1ꢀb]thiazole derivatives. The
reactions exhibit some functional group tolerance and allow for the preparation of a number of 3ꢀ
substituted and 2,3ꢀdisubstituted benzo[4,5]imidazo[2,1ꢀb]thiazoles in moderate to excellent
yields. The importance of the imidazol[2,1ꢀb]ꢀthiazole derivatives would render this protocol
attractive for both synthetic and medicinal chemistry.
Experimental Section
General. All reagents and solvents were pure analytical grade materials purchased from
commercial sources and were used without further purification, if not stated otherwise. All
melting points are uncorrected. All starting substrates were prepared according to the known
literatures. The NMR spectra were recorded in CDCl3 on a 400 MHz instrument with TMS as
internal standard. Highꢀresolution mass spectra (HRMS) were obtained with a QꢀTOF Premier
(ESI). TLC was carried out with 0.2 mm thick silica gel plates (GF254). Visualization was
accomplished by UV light. Column chromatography was hand packed with silica gel (200ꢀ300
mesh). All reactions were carried out in an overꢀdried Schlenk tube equipped with a magnetic stir
bar.
General procedure for the synthesis of 3-substituted benzo[4,5]imidazo[2,1-b]thiazoles
1cꢀ27c. An ovenꢀdried Schlenk tube equipped with a Teflon valve was charged with a magnetic
stir bar, CuI (0.075 mmol), 1,10ꢀPhen (0.15 mmol), transꢀ1,2ꢀdiiodoalkenes a (0.5 mmol), 1Hꢀ
benzo[d]imidazoleꢀ2ꢀthiols b (0.5 mmol) and K2CO3 (1.0 mmol). The tube was placed under
vacuum for twenty minutes and backfilled with N2, then DMF (2.0 mL) was added via syringe.
o
The reaction mixture was stirred at 100 C for 24 h. The reaction was monitored by TLC. When
1Hꢀbenzo[d]imidazoleꢀ2ꢀthiols b consumed completely, the reaction was stopped and 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
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column chromatography on silica gel using petrol/EtOAc (3:1, v:v) as eluent to give c.
General procedure for the synthesis of 2,3-disubstituted benzo[4,5]imidazo[2,1-
b]thiazoles 1d-16d. An ovenꢀdried Schlenk tube equipped with a Teflon valve was charged with
a magnetic stir bar, Pd(OAc)2 (0.015 mmol), PPh3 (0.03 mmol), 3ꢀphenylbenzo[4,5]imidazo[2,1ꢀ
b]thiazoles c (0.3 mmol), iodobenzenes f (0.40 mmol) and Cs2CO3 (0.6 mmol). The tube was
placed under vacuum for twenty minutes and backfilled with N2, then pꢀxylene (2.0 mL) was
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added via syringe. The reaction mixture was stirred at 135 C for 24 h. The reaction was
monitored by TLC. When 3ꢀphenylbenzo[4,5]imidazo[2,1ꢀb]thiazoles c consumed completely,
the reaction was stopped and cooled to room temperature, then the resulting suspension was
filtered through a pad of filter paper with 20 mL of ethyl acetate for 3 times. After evaporating
the solvent under reduced pressure, the residue was purified by column chromatography on silica
gel using petrol/EtOAc (4:1, v:v) as eluent to give d.
Typical procedure for the application of the Suzuki-coupling reaction. An ovenꢀdried
Schlenk tube equipped with a Teflon valve was charged with a magnetic stir bar, Pd(PPh3)4,
(0.015 mmol), 3ꢀ(2ꢀbromophenyl)benzo[4,5]imidazo[2,1ꢀb]thiazole 9c (0.3 mmol), pꢀ
tolylboronic acid (0.36 mmol). The tube was placed under vacuum for twenty minutes and
backfilled with N2, then 2M Na2CO3 (0.3 mL, 0.6 mmol), toluene (0.5 mL), EtOH (0.5 mL) were
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added via syringe. The reaction mixture was stirred at 100 C for 24 h. The reaction was
monitored by TLC. When 3ꢀ(2ꢀbromophenyl)benzo[4,5]imidazo[2,1ꢀb]thiazole 9c (0.3 mmol)
consumed completely, the reaction was stopped and cooled to room temperature, then the
resulting suspension was filtered through a pad of filter paper with 20 mL of ethyl acetate, then
the aqueous layer was removed by a separatory funnel. The organic phase was dried over
Na2SO4 and concentrated, the residue was purified by column chromatography on silica gel
using petrol/EtOAc (4:1, v:v) as eluent to give 17d.
3ꢀPhenylbenzo[4,5]imidazo[2,1ꢀb]thiazole19(1c). Yellow solid (61.5 mg, 82% yield), mp: 138ꢀ
139 °C (Lit. mp: 138ꢀ140 °C). 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.0 Hz, 1H), 7.67ꢀ7.64
(m, 2H), 7.58ꢀ7.57 (m, 3H), 7.32 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.06 (t, J = 8.0 Hz,
1H), 6.60 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 157.3, 148.8, 134.4, 130.2, 130.2, 129.5,
129.1, 129.0, 123.5, 120.6, 119.3, 111.8, 107.3.
3ꢀ(oꢀTolyl)benzo[4,5]imidazo[2,1ꢀb]thiazole (2c). Yellow solid (63.4 mg, 80% yield), mp:
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104ꢀ108 C. H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.4 Hz, 1H), 7.52 (t, J = 7.6 Hz,
1H),7.45ꢀ7.35 (m, 3H), 7.29 (t, J = 7.6 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.70 (dd, J1 = 0.8 Hz, J2
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= 8.4 Hz, 1H), 6.58 (d, J = 0.8 Hz, 1H), 2.20 (s, 3H). C NMR (100 MHz, CDCl3): δ 156.7,
148.6, 138.4, 133.0, 130.8, 130.7, 130.6, 130.1, 129.0, 126.5, 123.4, 120.8, 119.1, 110.7, 107.1,
19.7. HRMS (ESI): m/z calcd for C16H13N2S [M+H]+: 265.0799; found: 265.0770.
3ꢀ(mꢀTolyl)benzo[4,5]imidazo[2,1ꢀb]thiazole (3c). Yellow solid (61.8 mg, 78% yield), mp:
164ꢀ168 oC. 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.0 Hz, 1H), 7.46ꢀ7.38 (m, 4H), 7.32 (t,
J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.57 (s, 1H), 2.46 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 157.4, 148.8, 139.0, 134.5, 131.0, 130.2, 129.6, 129.4, 128.9, 126.0,
123.4, 120.5, 119.3, 111.9, 107.0, 21.6. HRMS (ESI): m/z calcd for C16H13N2S [M+H]+:
265.0799; found: 265.0777.
3ꢀ(pꢀTolyl)benzo[4,5]imidazo[2,1ꢀb]thiazole19 (4c). Yellow solid (63.4 mg, 80% yield), mp:
118ꢀ120 oC (Lit. mp: 118ꢀ121 °C). 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.0 Hz, 1H), 7.54
(d, J = 8.0 Hz, 2H), 7.38ꢀ7.30 (m, 3H), 7.25 (d, J = 8.0 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.56 (s,
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1H), 2.50 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 157.4, 148.7, 140.5, 134.5, 130.2, 129.8,
128.9, 126.6, 123.5, 120.5, 119.3, 111.9, 106.9, 21.6.
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3ꢀ(4ꢀButylphenyl)benzo[4,5]imidazo[2,1ꢀb]thiazole (5c). Yellow liquid (76.2 mg, 83% yield),
mp: 61ꢀ63 oC. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H),
7.36 (d, J = 8.0 Hz, 2H), 7.31 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.06 (t, J = 7.6 Hz,
1H), 6.53 (s, 1H), 1.74ꢀ1.66 (m, 2H), 1.46ꢀ1.41 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 157.3, 148.8, 145.4, 134.5, 130.2, 129.0, 128.8, 126.7, 123.4, 120.4, 119.2,
111.9, 106.7, 35.7, 33.5, 22.5, 14.1. HRMS (ESI): m/z calcd for C19H19N2S [M+H]+: 307.1269;
found: 307.1280.
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3ꢀ(4ꢀ(tertꢀButyl)phenyl)benzo[4,5]imidazo[2,1ꢀb]thiazole (6c). Yellow solid (72.5 mg, 79%
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yield), mp: 116ꢀ117 C. 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J = 8.4 Hz, 1H), 7.58 (m, 4H),
7.34ꢀ7.26 (m, 2H), 7.08 (t, J = 8.0 Hz, 1H), 6.55 (s, 1H), 1.42 (s, 9H). 13C NMR (100 MHz,
CDCl3): δ 157.4, 153.6, 148.8, 134.5, 130.2, 128.6, 126.5, 126.0, 123.4, 120.5, 119.2, 112.0,
106.9, 35.1, 31.4. HRMS (ESI): m/z calcd for C19H19N2S [M+H]+: 307.1269; found: 307.1268.
3ꢀ(4ꢀFluorophenyl)benzo[4,5]imidazo[2,1ꢀb]thiazole (7c). Yellow solid (58.7 mg, 73% yield);
mp: 174ꢀ177 oC. 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.0 Hz, 1H), 7.67ꢀ7.63 (m, 2H),
7.36ꢀ7.26 (m, 3H), 7.17 (d, J = 8.0 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 6.61 (s, 1H). 13C NMR (100
MHz, CDCl3): δ 163.83 (d, J = 249 Hz), 157.3, 148.9, 133.2, 131.0 (d, J = 8.3 Hz), 130.2, 125.6
(d, J = 3.6 Hz), 123.5, 120.6, 119.5, 116.3 (d, J = 21.9 Hz), 111.5, 107.5.
3ꢀ(4ꢀChlorophenyl)benzo[4,5]imidazo[2,1ꢀb]thiazole19 (8c). Yellow solid (60.5 mg, 71%
yield), mp: 200ꢀ202 oC (Lit. mp: 199ꢀ201 °C). 1H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 8.4 Hz,
1H), 7.63ꢀ7.56 (m, 4H), 7.36 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.11 (t, J = 7.2 Hz,
1H), 6.65 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 157.2, 148.7, 136.5, 133.2, 132.8, 130.2,
129.5, 127.9, 123.7, 120.8, 119.5, 111.6, 108.0. HRMS (ESI): m/z calcd for C15H10ClN2S
[M+H]+: 285.0253; found: 285.0256.
3ꢀ(2ꢀBromophenyl)benzo[4,5]imidazo[2,1ꢀb]thiazole (9c). Yellow solid (70.8 mg, 72% yield),
mp: 164ꢀ167 oC. 1H NMR (400 MHz, CDCl3): δ 7.82ꢀ7.77 (m, 2H), 7.56ꢀ7.46 (m, 3H), 7.31 (t, J
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= 7.6 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.69 (s, 1H). C NMR (100
MHz, CDCl3): δ 156.4, 148.5, 133.5, 132.5, 132.1, 132.0, 130.8, 130.1, 128.0, 124.7, 123.5,
120.8, 119.2, 111.0, 108.9. HRMS (ESI): m/z calcd for C15H10BrN2S [M+H]+: 328.9748; found:
328.9757.
3ꢀButylbenzo[4,5]imidazo[2,1ꢀb]thiazole19 (10c). Yellow solid (53.8 mg, 78% yield), mp: 85ꢀ
86 oC (Lit. mp: 85ꢀ87 °C). 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.0 Hz, 1H), 7.66 (d, J =
8.0 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 6.26 (s, 1H), 2.97 (t, J = 7.6 Hz,
2H), 1.81ꢀ1.74 (m, 2H), 1.54ꢀ1.46 (m, 2H), 0.99 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 157.5, 148.6, 134.6, 130.1, 123.2, 120.7, 119.2, 110.9, 103.8, 28.9, 28.1, 22.3, 13.8.
3ꢀBenzylbenzo[4,5]imidazo[2,1ꢀb]thiazole20 (11c). Brown solid (62.6 mg, 79% yield), mp: 80ꢀ
83 oC (Lit. mp: 82ꢀ83 °C). 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.4 Hz, 1H), 7.61 (d, J =
13
8.4 Hz, 1H), 7.40ꢀ7.29 (m, 6H), 7.16 (t, J = 8.0 Hz, 1H), 6.16 (s, 1H), 4.40 (s, 2H). C NMR
(100 MHz, CDCl3): δ 157.5, 148.5, 135.0, 133.3, 130.2, 129.2, 128.9, 127.7, 123.4, 120.9, 119.3,
111.1, 106.7, 34.8. HRMS (ESI): m/z calcd for C16H13N2S [M+H]+: 265.0799; found: 265.0798.
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3ꢀCyclopropylbenzo[4,5]imidazo[2,1ꢀb]thiazole (12c). Yellow solid (46.9 mg, 73% yield),
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mp: 101ꢀ103 C. H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz,
1H), 7.38 (t, J = 7.6 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 6.31 (d, J = 1.6 Hz, 1H), 2.23ꢀ2.18 (m,
1H), 1.19ꢀ1.15 (m, 2H), 0.92ꢀ0.88 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 157.1, 148.6, 136.0,
130.4, 123.5, 120.8, 119.2, 111.5, 104.8, 8.9, 6.3. HRMS (ESI): m/z calcd for C12H11N2S [M+H]+:
215.0643; found: 215.0640.
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3ꢀ(Pyridinꢀ3ꢀyl)benzo[4,5]imidazo[2,1ꢀb]thiazole (13c). Yellow solid (49.7 mg, 66% yield),
mp: 132ꢀ134 oC. 1H NMR (400 MHz, CDCl3): δ 8.93 (d, J = 1.2 Hz, 1H), 8.82 (dd, J1 = 1.2 Hz,
J2 = 5.6 Hz, 1H), 8.00 (td, J1 = 1.2 Hz, J2 = 8.0 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.52 (dd, J1 =
4.8 Hz, J2 = 8.0 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.08 (t, J = 8.0 Hz,
1H), 6.70 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 156.3, 148.3, 133.4, 132.3, 132.0, 130.6,
129.9, 127.9, 124.6, 123.4, 120.8, 119.0, 110.9, 108.8.
6ꢀMethylꢀ3ꢀphenylbenzo[4,5]imidazo[2,1ꢀb]thiazole
(14c)
and
7ꢀmethylꢀ3ꢀ
phenylbenzo[4,5]imidazo[2,1ꢀb]thiazole (15c). Yellow solid (65.7 mg, 83% yield, ratio = 1:1.2).
1H NMR (400 MHz, CDCl3): δ 7.67ꢀ7.63 (m, 5H), 7.57ꢀ7.55 (m, 7H), 7.14 (d, J = 8.4 Hz, 1H),
7.10 (d, J = 8.4 Hz, 1H), 7.00 (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.54 (s, 2H), 2.47 (s, 3H), 2.35 (s,
3H). HRMS (ESI): m/z calcd for C16H13N2S [M+H]+: 265.0799; found: 265.0796.
6ꢀChloroꢀ3ꢀphenylbenzo[4,5]imidazo[2,1ꢀb]thiazole
(16c)
and
7ꢀchloroꢀ3ꢀ
phenylbenzo[4,5]imidazo[2,1ꢀb]thiazole (17c). Yellow solid (63.9 mg, 75% yield, ratio = 1:1.2).
1H NMR (400 MHz, CDCl3): δ 7.75 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.64ꢀ7.57 (m, 10H), 7.29
(dd, J1 = 2.0 Hz, J2 = 8.4 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.02 (dd, J1
= 2.0 Hz, J2 = 8.4 Hz, 1H), 6.623 (s, 1H), 6.618 (s, 1H). HRMS (ESI): m/z calcd for
C15H10ClN2S [M+H]+: 285.0253; found: 285.0251.
6ꢀMethylꢀ3ꢀ(pꢀtolyl)benzo[4,5]imidazo[2,1ꢀb]thiazole
(18c)
and
7ꢀmethylꢀ3ꢀ(pꢀ
tolyl)benzo[4,5]imidazo [2,1ꢀb]thiazole (19c). Yellow solid (69.2 mg, 83% yield, ratio = 1:1.2).
1H NMR (400 MHz, CDCl3): δ 7.65 (d, J = 8.4 Hz, 1H), 7.56ꢀ7.51 (m, 5H), 7.38ꢀ7.35 (m, 4H),
7.14 (d, J = 8.4 Hz, 2H), 7.06 (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.503 (s, 1H), 6.497 (s, 1H), 2.50
(s, 3H), 2.49 (s, 3H), 2.47 (s, 3H), 2.37 (s, 3H). HRMS (ESI): m/z calcd for C17H15N2S [M+H]+:
279.0956; found: 279.0955.
3ꢀ(4ꢀChlorophenyl)ꢀ6ꢀmethylbenzo[4,5]imidazo[2,1ꢀb]thiazole (20c) and 3ꢀ(4ꢀchlorophenyl)ꢀ
7ꢀmethylbenzo[4,5]imidazo[2,1ꢀb]thiazole (21c). Yellow solid (65.3 mg, 73% yield, ratio =
1
1:1.2). H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.4 Hz, 1H), 7.62ꢀ7.54 (m, 9H), 7.16 (d, J =
8.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.01 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.59 (s, 1H), 6.58 (s,
1H), 2.48 (s, 3H), 2.39 (s, 3H). HRMS (ESI): m/z calcd for C16H12ClN2S [M+H]+: 299.0410;
found: 299.0411.
6ꢀChloroꢀ3ꢀ(pꢀtolyl)benzo[4,5]imidazo[2,1ꢀb]thiazole (22c). Yellow solid (30.5 mg, 34.1%
yield), mp: 175ꢀ176 oC. 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.0
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Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.30ꢀ7.24 (m, 2H), 6.57 (s, 1H), 2.50 (s, 3H). C NMR (100
MHz, CDCl3): δ 158.1, 147.4, 140.8, 134.3, 123.0, 129.9, 128.8, 128.7, 126.1, 124.1, 120.0,
112.0, 107.4, 21.7. HRMS (ESI): m/z calcd for C16H12ClN2S [M+H]+: 299.0410; found:
299.0405.
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7ꢀChloroꢀ3ꢀ(pꢀtolyl)benzo[4,5]imidazo[2,1ꢀb]thiazole (23c). Yellow solid (36.6 mg, 40.9 %
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yield), mp: 178ꢀ179 C. H NMR (400 MHz, CDCl3): δ 7.76 (s, 1H), 7.52 (d, J = 8.0 Hz, 2H),
7.38 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H) , 6.58 (s, 1H), 2.45 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 159.3, 149.8, 140.7, 134.4, 130.09, 129.9, 129.1, 128.8,
126.2, 120.9, 119.0, 112.5, 107.4, 21.7. HRMS (ESI): m/z calcd for C16H12ClN2S [M+H]+:
299.0410; found: 299.0409.
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6ꢀChloroꢀ3ꢀ(4ꢀchlorophenyl)benzo[4,5]imidazo[2,1ꢀb]thiazole (24c). Yellow solid (30.2 mg,
31.8% yield), mp: 219ꢀ221 oC. 1H NMR (400 MHz, CDCl3): δ 7.71 (d, J = 8.8 Hz, 1H), 7.59 (m,
4H), 7.32 (d, J = 7.2 Hz, 1H), 7.21 (s, 1H), 6.67 (s, 1H). C NMR (100 MHz, CDCl3): δ 158.2,
13
148.9, 136.8, 133.2, 130.2, 129.7, 129.6, 128.5, 127.5, 121.3, 119.1, 112.3, 108.7. HRMS (ESI):
m/z calcd for C15H9Cl2N2S [M+H]+: 318.9863; found: 318.9862.
7ꢀChloroꢀ3ꢀ(4ꢀchlorophenyl)benzo[4,5]imidazo[2,1ꢀb]thiazole (25c). Yellow solid (36.4 mg,
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38.2 %yield), mp: 240ꢀ244 C. H NMR (400 MHz, CDCl3): δ 7.78 (s, 1H), 7.58 (m, 4H), 7.12
(d, J = 8.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.68 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 157.8,
146.7, 136.9, 133.1, 130.1, 129.8, 129.7, 127.3, 126.7, 124.6, 120.0, 111.8, 108.9. HRMS (ESI):
m/z calcd for C15H9Cl2N2S [M+H]+: 318.9863; found: 318.9866.
6, 7ꢀDifluoroꢀ3ꢀ(pꢀtolyl)benzo[4,5]imidazo[2,1ꢀb]thiazole (26c). Yellow solid (68.4 mg, 76%
o
yield), mp: 202ꢀ206 C. 1H NMR (400 MHz, CDCl3): δ 7.54ꢀ7.48 (m, 3H), 7.38 (d, J = 7.6 Hz,
13
2H), 7.03 (t, J = 8.4 Hz, 1H), 6.58 (s, 1H), 2.49 (s, 3H). C NMR (100 MHz, CDCl3): δ 158.3,
148.3 (q, J1 = 14.9 Hz, J2 = 241.5 Hz), 146.0 (q, J1 = 15.4 Hz, J2 = 240.2 Hz), 144.2 (d, J = 10.4
Hz), 140.9, 134.0, 130.0, 128.7, 125.9, 125.1 (d, J = 10.8 Hz), 107.3, 106.5 (d, J = 19.8 Hz),
100.2 (d, J = 24.0 Hz), 21.6. HRMS (ESI): m/z calcd for C16H11F2N2S [M+H]+: 301.0611; found:
301.0615.
3ꢀ(4ꢀChlorophenyl)ꢀ6,7ꢀdifluorobenzo[4,5]imidazo[2,1ꢀb]thiazole (27c). Yellow solid (68.2
o
mg, 71% yield), mp: 168ꢀ172 C. 1H NMR (400 MHz, CDCl3): δ 7.59ꢀ7.52 (m, 5H), 7.01 (t, J =
13
8.4 Hz, 1H), 6.65 (s, 1H). C NMR (100 MHz, CDCl3): δ 158.2, 148.4 (q, J1 = 14.7 Hz, J2 =
242.6 Hz), 146.1 (q, J1 = 15.3 Hz, J2 = 241.0 Hz), 144.4, 136.9, 132.7, 130.1, 129.8, 128.2 (d, J
= 129.7 Hz), 127.3, 108.5, 106.7 (d, J = 20.0 Hz), 100.0 (d, J = 24.0 Hz). HRMS (ESI): m/z
calcd for C15H8ClF2N2S [M+H]+: 321.0065; found: 321.007.
2,3ꢀDiphenylbenzo[4,5]imidazo[2,1ꢀb]thiazole (1d). White solid (93.9 mg, 96% yield), mp:
196ꢀ197 °C. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.4 Hz, 1H), 7.60ꢀ7.55 (m, 5H), 7.31ꢀ
7.27 (m, 6H), 6.99 (t, J = 8.0 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ
154.7, 148.1, 131.4, 130.6, 130.4, 130.3, 129.5, 129.1, 128.8, 128.7, 128.4, 128.3, 123.7, 123.4,
120.6, 119.1, 111.5. HRMS (ESI): m/z calcd for C21H15N2S [M+H]+: 327.0956; found: 327.0960.
2ꢀPhenylꢀ3ꢀ(oꢀtolyl)benzo[4,5]imidazo[2,1ꢀb]thiazole (2d). Yellow solid (91.8 mg, 90%
yield), mp: 144ꢀ148 °C. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 7.2
Hz, 1H), 7.45ꢀ7.36 (m, 3H), 7.30ꢀ7.26 (m, 6H), 6.96 (t, J = 7.6 Hz, 1H), 6.47 (d, J = 8.0 Hz, 1H),
2.15 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 154.5, 148.0, 138.8, 131.7, 131.1, 130.8, 130.3,
129.0, 128.9, 128.5, 128.3, 127.8, 127.6, 127.1, 123.7, 123.5, 121.0, 119.1, 110.8, 19.6. HRMS
(ESI): m/z calcd for C22H17N2S [M+H]+: 341.1112; found: 341.1117.
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3ꢀ(4ꢀButylphenyl)ꢀ2ꢀphenylbenzo[4,5]imidazo[2,1ꢀb]thiazole (3d). Yellow solid (108.9 mg,
95% yield), mp: 108ꢀ112 °C. 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.4 Hz, 1H), 7.44 (d, J
= 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H),7.30ꢀ7.24 (m, 6H), 6.99 (t, J = 8.0 Hz, 1H), 6.78 (d, J =
8.0 Hz, 1H), 2.75 (t, J = 8.0 Hz, 2H), 1.75ꢀ1.68 (m, 2H), 1.48ꢀ1.39 (m, 2H), 0.99 (t, J = 7.6 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 154.8, 148.1, 145.4, 131.7, 130.5, 130.4, 129.5, 128.8,
128.70, 128.65, 128.2, 126.3, 123.4, 123.4, 120.6, 119.1, 111.6, 35.7, 33.4, 22.5, 14.1. HRMS
(ESI): m/z calcd for C25H23N2S [M+H]+: 383.1582; found: 383.1588.
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3ꢀ(4ꢀChlorophenyl)ꢀ2ꢀphenylbenzo[4,5]imidazo[2,1ꢀb]thiazole (4d). Yellow solid (97.2 mg,
90% yield), mp: 329ꢀ333 °C. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.4 Hz, 1H), 7.53 (d, J
= 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.32ꢀ7.23 (m, 6H), 7.02 (t, J = 8.0 Hz, 1H), 6.82 (d, J =
13
8.4 Hz, 1H). C NMR (100 MHz, CDCl3): δ 154.9, 148.2, 136.5, 132.0, 131.1, 130.3, 129.9,
129.0, 128.9, 128.6, 127.6, 127.1, 124.4, 123.6, 120.8, 119.3, 111.3. HRMS (ESI): m/z calcd for
C21H14ClN2S [M+H]+: 361.0566; found: 361.0566.
3ꢀ(2ꢀBromophenyl)ꢀ2ꢀphenylbenzo[4,5]imidazo[2,1ꢀb]thiazole (5d). White solid (112.7 mg,
93% yield), mp: 180ꢀ182 oC. 1H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 7.6 Hz, 1H), 7.79 (d, J
= 8.0 Hz, 1H), 7.52ꢀ7.44 (m, 3H), 7.32ꢀ7.26 (m, 6H), 7.00 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 8.0 Hz,
1H). 13C NMR (100 MHz, CDCl3): δ 154.3, 147.9, 133.6, 133.0, 132.2, 131.2, 130.9, 130.1,
129.0, 128.6, 128.5, 128.3, 126.8, 125.8, 125.2, 123.5, 121.0, 119.2, 110.8. HRMS (ESI): m/z
calcd for C21H14BrN2S [M+H]+: 405.0061; found: 405.0066.
3ꢀButylꢀ2ꢀphenylbenzo[4,5]imidazo[2,1ꢀb]thiazole (6d). White solid (78.0 mg, 85% yield),
mp: 116ꢀ120 °C. 1H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz,
1H), 7.49ꢀ7.36 (m, 6H), 7.27 (t, J = 7.6 Hz, 1H), 3.08 (t, J = 8.0 Hz, 2H), 1.88ꢀ1.80 (m, 2H),
1.52ꢀ1.43 (m, 2H), 0.94 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 155.7, 148.1, 131.8,
130.1, 130.0, 129.6, 129.1, 128.8, 123.4, 121.7, 121.0, 119.3, 111.0, 30.6, 26.1, 22.5, 13.8.
HRMS (ESI): m/z calcd for C19H19N2S [M+H]+: 307.1269; found: 307.1266.
3ꢀCyclopropylꢀ2ꢀphenylbenzo[4,5]imidazo[2,1ꢀb]thiazole (7d). White solid (69.6 mg, 80%
yield), mp: 124ꢀ126 °C. 1H NMR (400 MHz, CDCl3): δ 8.14 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.0
Hz, 1H), 7.59ꢀ7.57 (m, 2H), 7.50ꢀ7.42 (m, 4H), 7.35 (t, J = 8.0 Hz, 1H), 2.31ꢀ2.26 (m, 1H), 1.23ꢀ
1.18 (m, 2H), 0.64ꢀ0.59 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 153.6, 148.3, 130.9, 129.8,
129.5, 129.1, 128.9, 128.4, 124.6, 122.0, 118.0, 112.6, 110.1, 9.5, 7.6. HRMS (ESI): m/z calcd
for C18H15N2S [M+H]+: 291.0956; found: 291.0952.
6ꢀChloroꢀ3ꢀ(4ꢀchlorophenyl)ꢀ2ꢀphenylbenzo[4,5]imidazo[2,1ꢀb]thiazole (8d). Yellow solid
(92.2 mg, 78% yield), mp: 188ꢀ191 °C. 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 8.8 Hz, 1H),
7.55 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.31ꢀ7.21 (m, 6H), 6.83 (d, J = 2.0 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ 155.4, 146.7, 136.8, 131.9, 130.9, 130.4, 130.07, 129.1, 129.0,
128.9, 127.0, 126.9, 126.4, 125.2, 124.2, 120.1, 111.5. HRMS (ESI): m/z calcd for C21H13Cl2N2S
[M+H]+: 395.0176; found: 395.0169.
7ꢀChloroꢀ3ꢀ(4ꢀchlorophenyl)ꢀ2ꢀphenylbenzo[4,5]imidazo[2,1ꢀb]thiazole (9d). Yellow solid
(93.4 mg, 79% yield), mp: 209ꢀ213°C. 1H NMR (400 MHz, CDCl3): δ 7.74 (s, 1H), 7.54 (d, J =
8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.30ꢀ7.23 (m, 5H), 6.98 (d, J = 8.8 Hz, 1H), 6.73 (d, J =
13
8.8 Hz, 1H). C NMR (100 MHz, CDCl3): δ 155.9, 148.9, 136.7, 131.9, 130.8, 130.1, 123.0,
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129.2, 129.1, 128.9, 128.8, 127.2, 126.9, 125.1, 121.1, 119.0, 111.9. HRMS (ESI): m/z calcd for
C21H13Cl2N2S [M+H]+: 395.0176; found: 395.0175.
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6,7ꢀDifluoroꢀ2ꢀphenylꢀ3ꢀ(pꢀtolyl)benzo[4,5]imidazo[2,1ꢀb]thiazole (10d). Yellow solid (84.6
mg, 75% yield), mp: 194ꢀ195 °C. 1H NMR (400 MHz, CDCl3): δ 7.52 (t, J = 8.4 Hz, 1H), 7.40ꢀ
7.26 (m, 9H), 6.60 (t, J = 8.4 Hz, 1H), 2.50 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 155.8, 149.5
(d, J = 15.0 Hz), 147.2 (q, J1 = 15.0 Hz, J2 = 22.6 Hz ), 144.9 (d, J = 15.2 Hz), 143.6, 140.9,
131.3, 130.5, 130.3, 128.9, 128.8, 128.6, 128.1, 125.4, 124.2, 106.4 (d, J = 20.1 Hz), 99.9 (d, J =
24.0 Hz), 21.8. HRMS (ESI): m/z calcd for C22H15F2N2S [M+H]+: 377.0924; found: 377.0930.
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3ꢀPhenylꢀ2ꢀ(oꢀtolyl)benzo[4,5]imidazo[2,1ꢀb]thiazole (11d). White solid (91.8 mg, 90%
yield), mp: 150ꢀ155 °C. 1H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 8.0 Hz, 1H), 7.47ꢀ7.40 (m,
5H), 7.35ꢀ7.31 (m, 2H), 7.25 (d, J = 7.2 Hz, 1H), 7.18ꢀ7.15 (m, 2H), 7.03 (d, J = 7.6 Hz, 2H),
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2.18 (s, 3H). C NMR (100 MHz, CDCl3): δ 155.8, 148.0, 138.3, 132.2, 130.5, 130.3, 130.00,
129.97, 129.85, 129.8, 129.5, 128.9, 128.7, 126.0, 123.4, 122.9, 120.5, 119.2, 111.8, 20.3.
HRMS (ESI): m/z calcd for C22H17N2S [M+H]+: 341.1112; found: 341.1118.
3ꢀPhenylꢀ2ꢀ(mꢀtolyl)benzo[4,5]imidazo[2,1ꢀb]thiazole (12d). White solid (92.8 mg, 91%
o
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yield), mp:165ꢀ167 C. H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.0 Hz, 1H), 7.60ꢀ7.55 (m,
5H), 7.31ꢀ7.26 (m, 2H), 7.14ꢀ6.96 (m, 4H), 6.76 (d, J = 8.0 Hz, 1H), 2.27 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 154.9, 148.0, 138.6, 131.4, 130.7, 130.4, 130.3, 129.5, 129.5, 129.5, 129.3,
129.2, 128.7, 125.9, 124.1, 123.5, 120.7, 119.2, 111.5, 21.5. HRMS (ESI): m/z calcd for
C22H17N2S [M+H]+: 341.1112; found: 341.1119.
3ꢀPhenylꢀ2ꢀ(pꢀtolyl)benzo[4,5]imidazo[2,1ꢀb]thiazole (13d). White solid (91.8 mg, 90%
yield), mp: 211ꢀ212°C. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 8.4 Hz, 1H), 7.59ꢀ7.55 (m,
4H), 7.32ꢀ7.26 (m, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.99 (t, J = 8.0 Hz,
1H), 6.75 (d, J = 8.4 Hz, 1H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 154.6, 147.4, 138.6,
130.7, 130.7, 130.3, 129.6, 129.6, 129.5, 129.2, 128.7, 128.0, 124.4, 123.6, 120.8, 119.0, 111.6,
21.4. HRMS (ESI): m/z calcd for C22H17N2S [M+H]+: 341.1112; found: 341.1114.
2ꢀ(4ꢀChlorophenyl)ꢀ3ꢀphenylbenzo[4,5]imidazo[2,1ꢀb]thiazole (14d). Yellow solid (99.4 mg,
92% yield), mp: 198ꢀ202 °C. 1H NMR (400 MHz, CDCl3): δ 7.77 (d, J = 8.0 Hz, 1H), 7.63ꢀ7.51
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(m, 5H), 7.30ꢀ7.15 (m, 5H), 6.98 (t, J = 8.0 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H). C NMR (100
MHz, CDCl3): δ 154.5, 148.1, 134.3, 130.6, 130.5, 130.5, 130.3, 130.0, 129.9, 129.6, 129.1,
128.8, 123.5, 122.4, 120.7, 119.2, 111.5. HRMS (ESI): m/z calcd for C21H14ClN2S [M+H]+:
361.0566; found: 361.0558.
3ꢀ(4ꢀChlorophenyl)ꢀ6ꢀmethylꢀ2ꢀphenylbenzo[4,5]imidazo[2,1ꢀb]thiazole (15d) and 3ꢀ(4ꢀ
chlorophenyl)ꢀ7ꢀmethylꢀ2ꢀphenylbenzo[4,5]imidazo[2,1ꢀb]thiazole (16d). Yellow solid (105.5
mg, 94% yield, ratio = 1:1.2). 1H NMR (400 MHz, CDCl3): δ 7.70ꢀ7.65 (m, 3H), 7.56ꢀ7.46 (m,
9H), 7.28ꢀ7.23 (m, 8H),7.12 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz,
1H), 6.62 (s, 1H), 2.45 (s, 3H), 2.33 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 154.6, 154.1, 148.4,
146.2, 136.37, 136.35, 133.4, 132.2, 132.11, 132.05, 132.0, 132.0, 131.2, 130.6, 130.3, 129.8,
129.7, 128.93, 128.88, 128.8, 128.6, 128.52, 128.50, 128.2, 127.6, 127.0, 125.0, 124.1, 124.0,
122.1, 119.1, 118.8, 111.3, 110.8, 21.9, 21.8. HRMS (ESI): m/z calcd for C22H16ClN2S [M+H]+:
375.0723; found: 375.0720.
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3ꢀ(4'ꢀMethylꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀyl)benzo[4,5]imidazo[2,1ꢀb]thiazole (17d). Yellow solid (72.4
mg, 71% yield), mp: 75ꢀ76 °C. 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 8.4 Hz, 1H), 7.66 (t, J
= 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.52 (t, J = 8.0 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.06ꢀ
6.99 (m, 3H), 6.94ꢀ6.89 (m, 3H), 6.37 (s, 1H), 2.21 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
156.6, 148.1, 143.0, 137.4, 136.6, 132.8, 131.1, 130.9, 130.8, 129.8, 129.1, 128.6, 127.60, 127.57,
123.5, 120.6, 118.9, 111.3, 108.3, 21.2. HRMS (ESI): m/z calcd for C22H17N2S [M+H]+:
341.1112; found: 341.1109.
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3ꢀ(4'ꢀMethylꢀ[1,1'ꢀbiphenyl]ꢀ2ꢀyl)ꢀ2ꢀphenylbenzo[4,5]imidazo[2,1ꢀb]thiazole
(18d).
Compound 18d was prepared in a similar manner as described for compound 17d. Yellow solid,
mp: 78ꢀ80 °C. 1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.4 Hz, 1H), 7.68ꢀ7.65 (m, 2H), 7.59ꢀ
7.51 (m, 2H), 7.30 (t, J = 7.6 Hz, 1H), 7.22ꢀ7.16 (m, 3H), 7.03ꢀ7.00 (m, 3H), 6.82ꢀ6.76 (m, 3H),
6.71 (d, J = 8.0 Hz, 2H), 2.19 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 154.6, 147.9, 143.7, 137.1,
136.6, 131.7 131.5, 131.1, 130.9, 130.2, 128.84, 128.79, 128.6, 128.1, 128.02, 127.96, 127.7,
127.5, 124.2, 123.4, 120.7, 119.0, 111.3, 21.1. HRMS (ESI): m/z calcd for C28H21N2S [M+H]+:
417.1425; found: 417.1428.
Acknowledgements
This work was financially supported by the National Natural Science Foundation of China (No.
21402079 and 20401094)
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
1
http://pubs.acs.org. H NMR and 13C NMR spectra of all products. Xꢀray Crystallographic
Structure of 1d.
References
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