Metal-Free Oxidative Deamination Cross-Coupling of Imidazo-heterocycles with 2-Aminobenzothiazoles

Article abstract of DOI:10.1055/s-0035-1560395

A metal-free oxidative deamination-cross-coupling of imidazoheterocycles with 2-aminobenzothiazoles in the presence of tert-butyl nitrite is reported for the first time. This simple protocol tolerates a wide range of functional groups to afford various benzothiazole-imidazoheterocycles in moderate to excellent yields, with the release of nitrogen and water as benign byproducts.

Full text of DOI:10.1055/s-0035-1560395

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, 687–696
paper
687
X.-M. Ji et al.
Paper
Synthesis
Metal-Free Oxidative Deamination Cross-Coupling of Imidazo-
heterocycles with 2-Aminobenzothiazoles
Xiao-Ming Jia,b
R
Li Xua
Yun Yana
Fan Chenb
Ri-Yuan Tang*a
N
N
N
S
N
t-BuONO
+
R
NH2
Het
S
N
N
metal-free
Het
H
R = aryl, alkyl
Het = thiazole, benzothiazole, pyridine, pyrimidine
31 examples
up to 95% yield
a Department of Applied Chemistry, College of Materials and
Energy, South China Agricultural University, Guangzhou
510642, P. R. of China
b College of Chemistry and Materials Engineering, Wenzhou
University, Wenzhou 325035, P. R. of China
rytang@scau.edu.cn
Received: 22.10.2015
Accepted after revision: 11.12.2015
Published online: 05.01.2016
imidazoheterocycles. However, metal-catalyzed C–H activa-
tions commonly require noble-metal catalysts and excesses
of metal oxidants, which are generally expensive and harm-
ful to the environment. These environmental and economic
concerns necessitate the development of a metal-free C–H
functionalization strategy that meets the guiding principles
of green chemistry.14 We speculated that 1,3-benzothiazol-
2-amine might be an alternative reaction partner for the
formation of benzothiazole–imidazoheterocycles because it
can undergo a Sandmeyer reaction to afford a benzothi-
azolyl free-radical species.15 It has also been reported that a
variety of transformations can be carried out by using aryl
free-radicals formed from aryl diazonium salts.16,17 Howev-
er, C–H heteroarylations between two different heterocy-
cles, such as 2-aminobenzothiazoles and imidazoheterocy-
cles through a Meerwein heteroarylation strategy remains
to be developed. We therefore decided to develop a simple,
practicable, and metal-free method for the oxidative deam-
ination cross-coupling of imidazoheterocycles with 2-ami-
nobenzothiazoles under mild reaction conditions (Figure
1).
DOI: 10.1055/s-0035-1560395; Art ID: ss-2015-h0616-op
Abstract A metal-free oxidative deamination–cross-coupling of imid-
azoheterocycles with 2-aminobenzothiazoles in the presence of tert-bu-
tyl nitrite is reported for the first time. This simple protocol tolerates a
wide range of functional groups to afford various benzothiazole–imid-
azoheterocycles in moderate to excellent yields, with the release of ni-
trogen and water as benign byproducts.
Key words cross-coupling, heterocycles, imidazoles, benzothiazoles,
heteroarylation
Imidazoheterocycles are privileged scaffolds with a
broad range of biological activities in drug discovery.1 These
compounds have been widely used as antiviral,2 antibacte-
rial,3 and anticancer agents,4 as well as in the treatment of
cystic fibrosis.5 Additionally, imidazoheterocycles can be
used as functional materials.6 Because of their versatility as
pharmaceuticals and functional materials, considerable ef-
forts have been made to prepare imidazoheterocyclic cores
and to modify imidazoheterocycles.7,8 As an economical
and straightforward synthetic method, the direct C–H ary-
lation of imidazoheterocycles has received much attention.9
However, reports of C–H heteroarylations of imidazohet-
erocycles remain scarce.
R
N
N
N
S
N
t-BuONO
+
R
NH2
Het
S
N
N
Het
N2 + H2O
H
It is also well known that benzothiazoles are useful in
the development of drugs and materials.10,11 Benzothi-
azole–imidazoheterocycles, formed by coupling of benzo-
thiazoles with imidazoheterocycles, are expected to have
significance in medicinal chemistry and in materials sci-
ence because these compounds potentially possess unique
chemical and physical properties due to their highly conju-
gated heterocyclic structures. Metal-catalyzed C–H activa-
tions12 or oxidative free-radical reactions13 of benzothi-
azoles are straightforward pathways to benzothiazole–
Figure 1 Cross-coupling of imidazoheterocycles with 2-aminothiazoles
Optimization studies were performed for the heteroary-
lation of 6-phenylimidazo[2,1-b][1,3]thiazole (1a) with 1,3-
benzothiazol-2-amine (2a) as a model reaction (Table 1).
Several solvents, including cyclohexane, toluene, DCE,
MeNO2, and DMF, were examined in the presence of 1.5
equivalents of t-BuONO at 100 °C (Table 1, entries 1–5). The
preferred solvent was DCE, which gave product 3a in 34%
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688
X.-M. Ji et al.
Paper
Synthesis
yield, along with a 27% yield of 5-nitroso-6-phenylimid-
azo[2,1-b][1,3]thiazole as a byproduct (entry 3). To our de-
light, the addition of a base, such as K3PO4, K2CO3, KOAc,
NaOAc, or CsOAc, successfully suppressed the nitrosylation
of 1a and remarkably improved the yield of 3a to 55–61%
(entries 6–10). KOAc was most effective base for this trans-
formation (entry 8), whereas the strong base t-BuOLi was
unsuitable for this reaction (entry 11). Generally, organic
bases such as Et3N, DBU, or DMAP were less effective than
inorganic bases (entries 12–14). The use of either one or
two equivalents of KOAc gave similar results (entries 8 and
15), whereas the use of 0.5 equivalents of KOAc slightly de-
creased the yield of 3a to 56% (entry 16). To improve the
yield of 3a further, the use of two equivalents of 2a and t-
BuONO increased the yield of 3a to 73% (entry 17). It was
pleasing to find that performing the reaction at 90 °C slight-
ly enhanced the yield of 3a to 78% (entry 18), whereas
when the reaction was conducted at 80 °C, the yield of 3a
decreased to 71% (entry 19). Importantly, a gram-scale re-
action also proceeded smoothly to afford product 3a in 71%
yield (entry 18).
With the optimized reaction conditions in hand (Table
1, entry 18), we examined the scope of the heteroarylation
of imidazothiazoles with 2-aminobenzothiazoles (Table 2).
6-Arylimidazo[2,1-b][1,3]thiazoles bearing either an elec-
tron-withdrawing or an electron-donating group on the
benzene ring reacted smoothly to give the corresponding
products 3b–g in moderate to good yields. In comparison
with the substrate with a methyl group, the methoxy-sub-
stituted substrate was less effective under the standard
conditions and gave product 3c in 52% yield. Halo substitu-
ents were well tolerated under the standard conditions. For
example, the substrate containing a bromo group gave
product 3d in 78% yield, whereas that containing a chloro
group gave product 3e in 83% yield. However, the fluoro-
substituted substrate was less effective, possibly as a result
of the electronegativity of the fluorine atom (product 3f).
Note that various functional groups could be introduced
into products 3p,r by disconnection of the carbon–halogen
bond. Despite the steric hindrance of the naphthyl group, a
53% yield of 3h was obtained. We also examined substitu-
ent effects on the thiazole ring (3i–m). The substrate with
an ester group on the thiazole ring performed well, afford-
ing product 3j in 71% yield. It is noteworthy that further
transformation could be made at the ester group. Signifi-
cantly, benzo[d]imidazo[2,1-b]thiazoles performed particu-
larly well, affording the target products 3k–m in excellent
yields. These substrates contain a tricyclic conjugated plane
that can stabilize the imidazole ring to facilitate the trans-
formation.
Table 1 Screening for Optimal Conditionsa
Ph
N
S
base
t-BuONO
N
S
N
N
S
Ph
NH2
+
N
N
solvent
S
H
1a
2a
3a
Entry
Base (equiv)
Solvent
Isolated yield (%)
1
–
cyclohexane
toluene
DCE
12
2
–
28
3
–
34
4
–
MeNO2
DMF
DCE
33
5
–
11
6
K3PO4 (2)
K2CO3 (2)
KOAc (2)
NaOAc (2)
CsOAc (2)
t-BuOLi (2)
Et3N (2)
DBU (2)
DMAP (2)
KOAc (1)
KOAc (0.5)
KOAc (1)
KOAc (1)
KOAc (1)
56
7
DCE
55
8
DCE
61
9
DCE
58
10
11
12
13
14
15
16
17b
DCE
59
DCE
trace
40
DCE
DCE
43
DCE
45
DCE
62
DCE
56
DCE
73
18b,c
19b,e
DCE
78 (71)d
71
DCE
a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), t-BuONO (1.5 equiv),
solvent (2 mL), 100 °C, 12 h.
b 2a (0.4 mmol, 2 equiv), t-BuONO (2 equiv).
c At 90 °C.
d Gram-scale reaction: 1a (1 g, 5 mmol), 2a (10 mmol, 2 equiv), t-BuONO
(10 mmol, 2 equiv), KOAc (5 mmol, 1 equiv), DCE (20 mL), 90 °C, 12 h.
e At 80 °C.
such as halo groups disfavored the reaction, leading to a de-
crease in the yield of product (3p–r). The nitro-substituted
substrate was ineffective in this reaction. It was pleasing to
find that 1,3-thiazole-2-amine was also suitable for this
transformation, providing product 3t in 57% yield.
The scope of imidazo[1,2-a]pyridines was also exam-
ined (Table 3). 2-Arylimidazo[1,2-a]pyridines with a meth-
yl, methoxy, phenyl, chloro, bromo, or fluoro group on the
benzene ring reacted well to afford the corresponding prod-
ucts 5a–g in moderate to good yields. Substrates with
methyl groups on the pyridine ring furnished the corre-
sponding products 5h–i in moderate yields. To our delight,
both 2-methylimidazo[1,2-a]pyridine and 2-ethylimid-
azo[1,2-a]pyridine were compatible with the reaction con-
ditions and gave products 5j and 5k in 58 and 51% yield, re-
spectively. It is noteworthy that the reaction of 2-phenylim-
idazo[1,2-a]pyrimidine also proceeded smoothly to give
product 5l in 68% yield. Generally, imidazothiazoles are
Subsequently, several other 2-aminobenzothiazoles
were subjected to this heteroarylation. 2-Aminobenzothi-
azoles with a methyl or methoxy electron-donating group
were well tolerated, giving products 3n and 3o in 74% and
75% yield, respectively. Electron-withdrawing substituents
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Synthesis
Table 2 The Scope of Imidazo[2,1-b]thiazolesa
R
KOAc (1 equiv)
N
S
N
S
N
S
N
t-BuONO (2 equiv)
N
NH2
R
+
S
N
DCE, 90 °C, 12 h
H
1
2
3
N
S
N
N
N
S
S
S
Br
Cl
O
N
N
N
N
S
S
S
S
N
N
N
N
3b, 70%
3c, 52%
3d, 78%
3e, 83%
S
N
N
N
S
S
N
N
S
CN
F
N
N
N
N
S
S
S
S
N
N
N
3i, 68%
3h, 53%
3f, 63%
3g, 62%
S
S
S
N
N
N
N
N
N
N
S
O
N
Cl
O
S
Et
S
S
S
N
N
N
N
3j, 71%
3k, 93%
3l, 92%
3m, 95%
S
N
N
N
S
N
S
N
S
N
N
N
S
S
S
N
S
N
N
N
O
Cl
Br
3p, 53%
3n, 74%
3o, 75%
3q, 38%
N
S
N
S
N
S
N
N
N
S
N
S
N
S
N
F
NO2
3t, 57%
3r, 35%
3s, 0%
a Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), t-BuONO ( 2 equiv), KOAc (1 equiv), solvent (2 mL), 90 °C, 12 h.
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Table 3 The Scope of Imidazo[1,2-a]pyridinesa
R2
KOAc (1 equiv)
N
S
N
S
N
N
t-BuONO (2 equiv)
R2
R1
NH2
+
N
N
DCE, 90 °C, 12 h
H
R1
4
2a
5
N
N
N
N
N
N
O
Ph
N
N
S
N
S
S
N
S
N
N
5a, 72%
5b, 68%
5c, 56%
5d, 56%
N
N
N
N
N
N
Br
Cl
F
N
N
S
N
S
S
N
S
N
N
5e, 58%
5f, 70%
5g, 56%
5h, 61%
N
N
N
N
N
N
N
N
N
S
S
S
N
S
N
N
N
5l, 68%
5i, 62%
5j, 58%
5k, 51%
a Reaction conditions: 4 (0.2 mmol), 2 (0.4 mmol), t-BuONO (2 equiv), KOAc (1 equiv), solvent (2 mL), 90 °C, 12 h.
more effective and provide higher yields than imidazopyri-
dines under the standard conditions. Note that the imidazo-
heterocycles were generally consumed completely, whereas
a portion of the 2-aminobenzothiazole was transformed
into benzothiazole under the standard conditions. Unfortu-
nately, 1,3-benzoxazole-2-amine was unsuitable for this re-
action. Treatment of imidazothiazole 1a with aniline gave a
diazo product rather than a phenylated product in the pres-
ence of t-BuONO (see Supporting Information). The conju-
gation of the N=N bond with the benzene ring might stabi-
lize the diazonium salt to facilitate the formation of the di-
azo compound.
To gain insight into the mechanism, several control ex-
periments were conducted (see Supporting Information).
The addition of a radical scavenger such as 1,1-diphenyleth-
ylene or TEMPO to the reaction mixture completely sup-
pressed the reaction. In the absence of 1a, 1,3-benzothi-
azol-2-amine reacted with t-BuONO in the presence of 1,1-
diphenylethylene or TEMPO to form 1,3-benzothiazole and
1,3-benzothiazol-2(3H)-one. It was demonstrated that ben-
zothiazole did not react with imidazoheterocycle 1a under
the standard conditions. These results suggest that the
present reaction involves a radical process. On the basis of
the present results and previous reports,16,17 a possible
mechanism is proposed in Scheme 1. 1,3-Benzothiazol-2-
amine reacts initially with t-BuONO to yield the diazonium
salt A in situ; this is followed by a deamination process to
generate free radical B and nitrogen. Intermediate B then
reacts with substrate 1a to produce intermediate C. Inter-
mediate C undergoes an electron exchange with another di-
azonium salt A to afford a carbocation D and another inter-
mediate B. Alternatively, intermediate A might react direct-
ly with 1a to form carbocation D. Finally, carbocation D
undergoes a dehydrogenation process to afford target prod-
uct 3a. It is noteworthy that in the reactions of substrate 1a,
the heteroarylation takes place selectively at the imidazole
ring rather than the thiazole ring. This is because the elec-
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Ph
N
S
N
1a
N
S
N
S
t-BuONO
NH2
N2
t-BuO
A
H2O
N2
+
N2
t-BuO
heat
t-BuO
Ph
Ph
N
S
N
N
N
N
N
S
N
S
H
S
S
t-BuOH
3a
D
B
S
N
N2
Ph
N
H
1a
N
S
Ph
N2
N
N
A
S
N
H
S
C
Scheme 1 A possible mechanism
tron-rich imidazole ring is more reactive than the thiazole
ring and because of greater stability of carbocation D as a
result of conjugation with the benzene ring.
vacuo, and the residue was purified by column chromatography (sili-
ca gel, hexane–EtOAc) to give a yellow solid; yield: 52.2 mg (78%); mp
166.2–167.1 °C.
IR (ATR): 3106, 2967, 1550, 1530, 1358, 1132, 1099, 867 cm–1
.
In summary, a metal-free strategy has been developed
for the introduction of benzothiazole moieties onto imid-
azoheterocycles by oxidative deamination of 2-aminoben-
zothiazoles. This finding offers a simple and practicable
method for the synthesis of a variety of highly conjugated
heterocycles that are expected to be significant in pharma-
ceuticals or materials. This study also opens a new window
for the application of the Sandmeyer reaction in C–H het-
eroarylation.
1H NMR (500 MHz, CDCl3): δ = 8.75 (d, J = 4.5 Hz, 1 H), 7.95 (d, J = 8.0
Hz, 1 H), 7.74–7.68 (m, 2 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.51–7.49 (m, 3
H), 7.43–7.40 (m, 1 H), 7.29–7.25 (m, 1 H), 6.95 (d, J = 4.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 156.7, 152.7, 152.0, 150.3, 133.5,
133.5, 129.7, 129.2, 128.6, 126.0, 124.8, 122.1, 122.0, 121.0, 118.7,
112.6.
LRMS (EI, 70 eV): m/z (%) = 333 (83), 332 (100), 248 (11), 166 (10),
108 (7).
HRMS (ESI): m/z [M + H]+ calcd for C18H12N3S2+: 334.0467; found:
334.0471.
1H and 13C NMR spectra were measured on a Bruker Avance-III 500
instrument (500 MHz for 1H, 125 MHz for 13C NMR) with CDCl3 or
DMSO-d6 as the solvent, and were referenced to internal TMS (δ = 0.0
ppm) as the standard. Mass spectra were measured on a Shimadzu
GC-MS-QP2010 Plus spectrometer (EI). HRMS (ESI) analyses were
performed on a Bruker micrOTOF-Q II instrument. IR spectra were re-
corded on a Nicolet IS10 spectrophotometer (ATR).
2-[6-(4-Tolyl)imidazo[2,1-b][1,3]thiazol-5-yl]-1,3-benzothiazole
(3b)
Yellow solid; yield: 48.3 mg (70%); mp 138.8–139.5 °C.
IR (ATR): 3068, 2932, 1556, 1523, 1338, 1036, 827 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.76 (d, J = 4.5 Hz, 1 H), 7.95 (d, J = 8.0
Hz, 1 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.61 (d, J = 8.0 Hz, 2 H), 7.43–7.40 (m,
1 H), 7.32–7.27 (m, 3 H), 6.95 (d, J = 4.5 Hz, 1 H), 2.46 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 157.0, 152.9, 152.2, 150.8, 139.4,
133.7, 130.8, 129.8, 129.5, 126.2, 124.9, 122.3, 122.2, 121.3, 118.8,
112.7, 21.6.
2-(6-Phenylimidazo[2,1-b][1,3]thiazol-5-yl)-1,3-benzothiazole
(3a); Typical Procedure
A 15-mL tube equipped with a Teflon cap and a magnetic stirring bar
was charged with substrate 1a (0.20 mmol). 1,3-Benzothiazol-2-
amine (2a; 0.40 mmol, 2.0 equiv), KOAc (0.20 mmol, 1.0 equiv), DCE
(2 mL), and t-BuONO (0.40 mmol, 2.0 equiv) were then added sequen-
tially. The tube was then capped and the mixture was stirred at 90 °C
for 12 h. The crude mixture was diluted with EtOAc, filtered through a
Celite pad, and washed with EtOAc. The filtrate was concentrated in
LRMS (EI, 70 eV): m/z (%) = 347 (73), 346 (100), 281 (13), 207 (29),
173 (9).
HRMS (ESI): m/z [M + H]+ calcd for C19H14N3S2+: 348.0624; found:
348.0632.
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2-[6-(4-Methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-1,3-ben-
LRMS (EI, 70 eV): m/z (%) = 351 (88), 350 (100), 281 (17), 253 (12), 73
zothiazole (3c)
(16).
HRMS (ESI): m/z [M + H]+ calcd for C18H11FN3S2+: 352.0373; found:
Yellow solid; yield: 37.9 mg (52%); mp 143.7–144.3 °C.
IR (ATR): 3056, 2961, 1545, 1527, 1275, 1179, 860 cm–1
.
352.0380.
1H NMR (500 MHz, CDCl3): δ = 8.78 (d, J = 4.5 Hz, 1 H), 7.97 (d, J = 8.0
Hz, 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.66–7.64 (m, 2 H), 7.45–7.42 (m, 1
H), 7.31–7.28 (m, 1 H), 7.07–7.02 (m, 2 H), 6.98 (d, J = 4.5 Hz, 1 H),
3.90 (s, 3 H).
4-[5-(1,3-Benzothiazol-2-yl)imidazo[2,1-b][1,3]thiazol-6-yl]ben-
zonitrile (3g)
Yellow solid; yield: 44.3 mg (62%); mp 226.4–227.6 °C.
IR (ATR): 3100, 2921, 2233, 1553, 1507, 1311, 1099, 845 cm–1
.
13C NMR (125 MHz, CDCl3): δ = 160.7, 157.1, 152.9, 152.1, 150.6,
133.6, 131.2, 126.2, 126.0, 124.9, 122.3, 122.2, 121.2, 118.7, 114.2,
112.5, 55.4.
1H NMR (500 MHz, CDCl3): δ = 8.71 (d, J = 4.5 Hz, 1 H), 8.01 (d, J = 8.0
Hz, 1 H), 7.89 (d, J = 8.0 Hz, 2 H), 7.78–7.75 (m, 3 H), 7.48 (t, J = 8.0 Hz,
1 H), 7.36 (t, J = 8.0 Hz, 1 H), 7.03 (d, J = 4.5 Hz, 1 H).
LRMS (EI, 70 eV): m/z (%) = 363 (100), 207 (7), 181 (8), 16 (10).
13C NMR (125 MHz, CDCl3): δ = 155.6, 152.6, 152.3, 147.5, 138.1,
133.3, 132.2, 130.2, 126.3, 125.3, 122.4, 121.6, 121.1, 118.9, 118.4,
113.3, 112.6.
HRMS (ESI): m/z [M + H]+ calcd for C19H14N3OS2+: 364.0573; found:
364.0578.
2-[6-(4-Bromophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-1,3-benzo-
LRMS (EI, 70 eV): m/z (%) = 358 (96), 357 (100), 281 (6), 179 (7), 73
thiazole (3d)
(8).
HRMS (ESI): m/z [M + H]+ calcd for C19H11N4S2+: 359.0420; found:
Brown solid; yield: 64.5 mg (78%); mp 205.9–206.5 °C.
IR (ATR): 3110, 2958, 1559, 1538, 1201, 1121, 835 cm–1
.
359.0421.
1H NMR (500 MHz, CDCl3): δ = 8.75 (d, J = 4.5 Hz, 1 H), 7.98 (d, J = 8.0
Hz, 1 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.65–7.61 (m, 4 H), 7.47–7.44 (m, 1
H), 7.34–7.31 (m, 1 H), 7.00 (d, J = 4.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 156.4, 152.9, 152.3, 149.0, 133.6,
132.6, 132.0, 131.5, 126.4, 125.2, 123.7, 122.4, 122.1, 121.3, 118.9,
113.1.
2-[6-(2-Naphthyl)imidazo[2,1-b][1,3]thiazol-5-yl]-1,3-benzothi-
azole (3h)
Yellow solid; yield: 40.5 mg (53%); mp 215.3–216.2 °C.
IR (ATR): 2952, 1556, 1510, 1269, 1172, 1030, 831 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.82 (d, J = 4.5 Hz, 1 H), 8.26 (s, 1 H),
7.98 (d, J = 8.0 Hz, 2 H), 7.94–7.88 (m, 2 H), 7.82 (dd, J = 8.0, 1.5 Hz, 1
H), 7.64 (d, J = 8.0 Hz, 1 H), 7.59–7.52 (m, 2 H), 7.45–7.41 (m, 1 H),
7.29–7.26 (m, 1 H), 7.00 (d, J = 4.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 156.9, 152.9, 152.3, 150.4, 133.8,
133.6, 133.3, 131.0, 129.5, 128.5, 127.9, 127.2, 126.8, 126.5, 126.3,
125.0, 122.3, 122.2, 121.3, 119.1, 112.9.
LRMS (EI, 70 eV): m/z (%) = 412 (89), 411 (85), 281 (41), 207 (100),
166 (10).
HRMS (ESI): m/z [M + H]+ calcd for C18H11BrN3S2+: 411.9572; found:
411.9575.
2-[6-(4-Chlorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-1,3-benzo-
thiazole (3e)
LRMS (EI, 70 eV): m/z (%) = 383 (100), 382 (72), 298 (10), 153 (6), 69
(5).
Yellow solid; yield: 60.9 mg (83%); mp 201.6–202.1 °C.
HRMS (ESI): m/z [M + H]+ calcd for C22H14N3S2+: 384.0624; found:
384.0632.
IR (ATR): 3106, 2961, 1563, 1540, 1202, 1109, 837, 765 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.73 (d, J = 4.5 Hz, 1 H), 7.96 (d, J = 8.0
Hz, 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.67 (d, J = 8.0 Hz, 2 H), 7.48–7.42 (m,
3 H), 7.30 (t, J = 7.5 Hz, 1 H), 6.98 (d, J = 4.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 156.1, 152.5, 152.0, 148.7, 135.1,
133.3, 131.9, 130.9, 128.7, 126.1, 124.9, 122.1, 121.8, 121.0, 118.6,
112.7.
2-(2-Methyl-6-phenylimidazo[2,1-b][1,3]thiazol-5-yl)-1,3-benzo-
thiazole (3i)
Yellow solid; yield: 47.3 mg (68%); mp 127.2–128.4 °C.
IR (ATR): 3113, 2958, 1558, 1529, 1360, 839 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.45 (s, 1 H), 7.97 (d, J = 8.0 Hz, 1 H),
7.72–7.67 (m, 3 H), 7.49–7.48 (m, 3 H), 7.44–7.40 (m, 1 H), 7.30–7.25
(m, 1 H), 2.51 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 157.0, 152.9, 151.6, 149.4, 133.8,
133.7, 129.9, 129.2, 128.7, 126.9, 126.2, 124.9, 122.3, 121.2, 118.6,
14.1.
LRMS (EI, 70 eV): m/z (%) = 367 (95), 366 (100), 207 (27), 281 (13),
166 (10).
HRMS (ESI): m/z [M + H]+ calcd for C18H11ClN3S2+: 368.0077; found:
368.0080.
2-[6-(4-Fluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-1,3-benzo-
thiazole (3f)
LRMS (EI, 70 eV): m/z (%) = 347 (82), 346 (100), 281 (15), 248 (9), 69
(8).
Yellow solid; yield: 44.1 mg (63%); mp 189.3–190.1 °C.
HRMS (ESI): m/z [M + H]+ calcd for C19H14N3S2+: 348.0624; found:
348.0632.
IR (ATR): 3069, 2938, 1543, 1520, 1231, 1150, 1089, 973 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.76 (d, J = 4.5 Hz, 1 H), 7.97 (d, J = 8.0
Hz, 1 H), 7.72–7.69 (m, 3 H), 7.44 (t, J = 7.5 Hz, 1 H), 7.30 (t, J = 7.5 Hz,
1 H), 7.19 (t, J = 8.5 Hz, 2 H), 6.98 (d, J = 4.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 163.2 (d, JC–F = 247.5 Hz), 156.6, 152.9,
152.2, 149.4, 133.6, 131.8 (d, JC–F = 8.4 Hz), 129.8 (d, JC–F = 3.3 Hz),
126.3, 125.1, 122.4, 122.1, 121.3, 118.9, 115.8 (d, JC–F = 21.5 Hz), 112.9.
Ethyl 5-(1,3-Benzothiazol-2-yl)-6-phenylimidazo[2,1-b][1,3]thi-
azole-2-carboxylate (3j)
Yellow solid; yield: 57.3 mg (71%); mp 148.5–149.7 °C.
IR (ATR): 3060, 2913, 1699, 1560, 1540, 1298, 1099, 936 cm–1
.
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1H NMR (500 MHz, CDCl3): δ = 9.4 (s, 1 H), 8.0 (d, J = 8.2 Hz, 1 H),
7.73–7.72 (m, 2 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.52–7.50 (m, 3 H), 7.45 (t,
J = 7.5 Hz, 1 H), 7.30 (t, J = 7.5 Hz, 1 H), 4.45 (q, J = 7.0 Hz, 2 H), 1.44 (t,
J = 7.0 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C22H13ClN3S2+: 418.0234; found:
418.0240.
6-Methyl-2-(6-phenylimidazo[2,1-b][1,3]thiazol-5-yl)-1,3-benzo-
13C NMR (125 MHz, CDCl3): δ = 161.2, 156.1, 152.7, 152.6, 151.3,
133.5, 133.1, 129.8, 129.7, 128.8, 128.0, 126.3, 125.2, 122.6, 122.2,
121.2, 119.0, 62.3, 14.3.
thiazole (3n)
Yellow solid; yield: 51.3 mg (74%); mp 182.3–183.6 °C.
IR (ATR): 3013, 2967, 1587, 1526, 1350, 1030, 835 cm–1
.
LRMS (EI, 70 eV): m/z (%) = 405 (100), 376 (39), 281 (25), 135 (16), 73
(55).
HRMS (ESI): m/z [M + H]+ calcd for C21H16N3O2S2+: 406.0678; found:
1H NMR (500 MHz, CDCl3): δ = 8.74 (d, J = 4.5 Hz, 1 H), 7.84 (d, J = 8.5
Hz, 1 H), 7.74–7.72 (m, 2 H), 7.50–7.47 (m, 4 H), 7.26–7.22 (m, 1 H),
6.96 (d, J = 4.5 Hz, 1 H), 2.43 (s, 3 H).
406.0671.
13C NMR (125 MHz, CDCl3): δ = 155.9, 152.0, 151.0, 150.1, 135.2,
133.9, 133.8, 130.0, 129.3, 128.7, 127.8, 122.1, 121.9, 121.0, 118.9,
112.7, 21.6.
3-(1,3-Benzothiazol-2-yl)-2-phenylimidazo[2,1-b][1,3]benzothi-
azole (3k)
LRMS (EI, 70 eV): m/z (%) = 347 (82), 346 (100), 281 (26), 208 (13), 73
(48).
HRMS (ESI): m/z [M + H]+ calcd for C19H14N3S2+: 348.0624; found:
348.0626.
Yellow solid; yield: 71.3 mg (93%); mp 201.2–202.3 °C.
IR (ATR): 3073, 2913, 1543, 1503, 1348, 1023, 945 cm–1
1H NMR (500 MHz, CDCl3): δ = 8.14 (d, J = 8.0 Hz, 1 H), 8.05–8.03 (m, 1
H), 7.79 (d, J = 8.0 Hz, 1 H), 7.64–7.49 (m, 4 H), 7.39 (t, J = 7.5 Hz, 1 H),
7.30–7.23 (m, 5 H).
.
6-Methoxy-2-(6-phenylimidazo[2,1-b]thiazol-5-yl)benzo[d]thi-
13C NMR (125 MHz, CDCl3): δ = 156.7, 152.9, 150.0, 149.5, 135.9,
133.2, 133.1, 130.0, 128.9, 128.4, 128.3, 126.3, 125.9, 125.6, 124.9,
123.8, 123.4, 121.5, 118.3, 115.6.
azole (3o)
Yellow solid; yield: 54.6 mg (75%); mp 188.5–189.2 °C.
IR (ATR): 3113, 2973, 1596, 1531, 1026, 827 cm–1
.
LRMS (EI, 70 eV): m/z (%) = 383 (87), 382 (100), 281 (19), 191 (17), 73
(19).
HRMS (ESI): m/z [M + H]+ calcd for C22H14N3S2+: 384.0624; found:
1H NMR (500 MHz, CDCl3): δ = 8.69 (d, J = 4.5 Hz, 1 H), 7.83 (d, J = 9.0
Hz, 1 H), 7.73–7.71 (m, 2 H), 7.50–7.48 (m, 3 H), 7.14 (d, J = 2.5 Hz, 1
H), 7.02 (dd, J = 9.0, 2.5 Hz, 1 H), 6.94 (d, J = 4.5 Hz, 1 H), 3.80 (s, 3 H).
384.0629.
13C NMR (125 MHz, CDCl3): δ = 157.7, 154.6, 151.8, 149.8, 147.4,
135.1, 133.8, 129.9, 129.2, 128.7, 122.9, 122.0, 118.8, 115.4, 112.6,
104.0, 55.8.
3-(1,3-Benzothiazol-2-yl)-7-methyl-2-phenylimidazo[2,1-
b][1,3]benzothiazole (3l)
LRMS (EI, 70 eV): m/z (%) = 363 (100), 181 (10), 160 (10), 95 (16), 69
(8).
HRMS (ESI): m/z [M + H]+ calcd for C19H14N3OS2+: 364.0573; found:
Yellow solid; yield: 72.9 mg (92%); mp 203.7–204.5 °C.
IR (ATR): 3035, 2956, 1527, 1458, 1230, 1031, 915 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.20 (d, J = 8.0 Hz, 1 H), 8.01 (d, J = 8.0
Hz, 1 H), 7.86 (d, J = 8.0 Hz, 1 H), 7.64–7.63 (m, 2 H), 7.60–7.56 (m, 1
H), 7.49 (s, 1 H), 7.47–7.44 (m, 1 H), 7.37–7.36 (m, 3 H), 7.12 (d, J = 8.0
Hz, 1 H), 2.43 (s, 3 H).
364.0578.
6-Bromo-2-(6-phenylimidazo[2,1-b][1,3]thiazol-5-yl)-1,3-benzo-
thiazole (3p)
13C NMR (125 MHz, CDCl3): δ = 156.8, 152.9, 149.9, 149.2, 135.9,
135.1, 133.1, 131.1, 130.0, 128.9, 128.3, 128.3, 127.0, 126.2, 125.6,
123.8, 123.3, 121.5, 118.3, 115.3, 21.0.
Brown solid; yield: 43.9 mg (53%); mp 172.6–173.5 °C.
IR (ATR): 3115, 2968, 1539, 1352, 1097, 831 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.71 (d, J = 4.5 Hz, 1 H), 8.08 (d, J = 2.0
Hz, 1 H), 7.71–7.69 (m, 2 H), 7.52–7.50 (m, 4 H), 7.36 (dd, J = 8.0, 2.0
Hz, 1 H), 6.99 (d, J = 4.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 158.4, 154.1, 152.6, 151.2, 133.5,
132.4, 129.9, 129.6, 128.9, 127.9, 125.1, 122.2, 122.1, 120.0, 118.6,
113.1.
LRMS (EI, 70 eV): m/z (%) = 397 (88), 396 (100), 248 (11), 121 (7), 77
(6).
HRMS (ESI): m/z [M + H]+ calcd for C23H16N3S2+: 398.0780; found:
398.0788.
3-(1,3-Benzothiazol-2-yl)-7-chloro-2-phenylimidazo[2,1-
b][1,3]benzothiazole (3m)
LRMS (EI, 70 eV): m/z (%) = 412 (100), 410 (81), 331 (10), 207 (10),
107 (12).
HRMS (ESI): m/z [M + H]+ calcd for C18H11BrN3S2+: 411.9572; found:
411.9579.
Yellow solid; yield: 79.2 mg (95%); mp 119.8–120.5 °C.
IR (ATR): 3106, 2913, 1540, 1510, 1102, 803 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.27 (d, J = 9.0 Hz, 1 H), 8.17 (d, J = 8.0
Hz, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.66–7.61 (m, 3 H), 7.58–7.55 (m, 1
H), 7.46–7.43 (m, 1 H), 7.39–7.36 (m, 3 H), 7.29 (dd, J = 9.0, 2.0 Hz, 1
H).
13C NMR (125 MHz, CDCl3): δ = 156.7, 153.0, 150.2, 150.1, 136.0,
133.2, 132.2, 131.7, 130.8, 129.3, 128.9, 128.6, 126.6, 126.5, 126.0,
123.6, 123.5, 121.7, 119.1, 117.0.
6-Chloro-2-(6-phenylimidazo[2,1-b][1,3]thiazol-5-yl)-1,3-benzo-
thiazole (3q)
Yellow solid; yield: 28.0 mg (38%); mp 217.3–218.1 °C.
IR (ATR): 2971, 1556, 1543, 1228, 1135, 881, 766 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.76 (d, J = 4.5 Hz, 1 H), 7.87 (d, J = 8.5
Hz, 1 H), 7.72–7.71 (m, 2 H), 7.66 (d, J = 2.0 Hz, 1 H), 7.53–7.52 (m, 3
H), 7.40 (dd, J = 8.5, 2.0 Hz, 1 H), 7.03 (d, J = 4.5 Hz, 1 H).
LRMS (EI, 70 eV): m/z (%) = 418 (6), 416 (100), 207 (8), 191 (9), 69
(12).
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13C NMR (125 MHz, CDCl3): δ = 157.0, 152.1, 151.1, 150.6, 134.5,
133.2, 130.3, 129.6, 129.2, 128.5, 126.7, 122.6, 121.8, 120.5, 118.2,
112.7.
1H NMR (500 MHz, CDCl3): δ = 9.99 (d, J = 7.0 Hz, 1 H), 8.04 (d, J = 8.0
Hz, 1 H), 7.75–7.70 (m, 2 H), 7.61 (d, J = 8.0 Hz, 2 H), 7.47–7.38 (m, 2
H), 7.32–7.29 (m, 3 H), 7.07–7.04 (m, 1 H), 2.47 (s, 3 H).
LRMS (EI, 70 eV): m/z (%) = 367 (88), 366 (100), 282 (7), 183 (9), 107
(5).
HRMS (ESI): m/z [M + H]+ calcd for C18H11ClN3S2+: 368.0077; found:
13C NMR (125 MHz, CDCl3): δ = 157.6, 152.7, 150.4, 146.2, 139.2,
133.6, 130.6, 129.8, 129.2, 127.9, 127.0, 125.9, 124.7, 122.2, 120.9,
117.1, 115.8, 113.6, 21.4.
368.0085.
LRMS (EI, 70 eV): m/z (%) = 341 (80), 340 (100), 253 (8), 135 (6), 73
(15).
HRMS (ESI): m/z [M + H]+ calcd for C21H16N3S+: 342.1059; found:
6-Fluoro-2-(6-phenylimidazo[2,1-b][1,3]thiazol-5-yl)-1,3-benzo-
thiazole (3r)
342.1055.
Yellow solid; yield: 24.8 mg (35%); mp 171.7–172.5 °C.
IR (ATR): 3061, 2942, 1539, 1231, 1142, 982, 758 cm–1
.
2-[2-(4-Methoxyphenyl)imidazo[1,2-a]pyridin-3-yl]-1,3-benzo-
thiazole (5c)
1H NMR (500 MHz, CDCl3): δ = 8.70 (d, J = 4.5 Hz, 1 H), 7.87 (dd,
J = 9.0, 5.0 Hz, 1 H), 7.71–7.69 (m, 2 H), 7.51–7.49 (m, 3 H), 7.34 (dd,
J = 8.0, 2.5 Hz, 1 H), 7.16–7.12 (m, 1 H), 6.97 (d, J = 4.5 Hz, 1 H).
Brown solid; yield: 39.9 mg (56%); mp 229.3–230.2 °C.
IR (ATR): 3071, 2965, 1539, 1517, 1073, 952, 832 cm–1
.
13C NMR (125 MHz, CDCl3): δ = 160.0 (d, JC–F = 244.0 Hz), 156.3 (d,
JC–F = 3.1 Hz), 152.0, 150.3, 149.2 (d, JC–F = 3.1 Hz), 134.4 (d, JC–F = 11.1
Hz), 133.2, 129.6, 129.2, 128.5, 122.8 (d, JC–F = 9.3 Hz), 121.7, 118.3,
114.4 (d, JC–F = 24.5 Hz), 112.6, 107.2 (d, JC–F = 26.8 Hz).
1H NMR (500 MHz, CDCl3): δ = 9.89 (d, J = 7.0 Hz, 1 H), 7.94 (d, J = 8.0
Hz, 1 H), 7.65–7.61 (m, 2 H), 7.55 (d, J = 9.0 Hz, 2 H), 7.36–7.29 (m, 2
H), 7.22–7.19 (m, 1 H), 6.95–6.94 (m, 3 H), 3.80 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 160.7, 157.8, 152.9, 150.3, 146.4,
133.7, 131.5, 128.1, 127.3, 126.1, 125.9, 124.9, 122.4, 121.1, 117.2,
115.9, 114.2, 113.7, 55.4.
LRMS (EI, 70 eV): m/z (%) = 351 (90), 350 (100), 306 (8), 279 (3), 103
(8).
HRMS (ESI): m/z [M + H]+ calcd for C18H11FN3S2+: 352.0373; found:
LRMS (EI, 70 eV): m/z (%) = 357 (100), 356 (97), 281 (39), 207 (75), 73
352.0386.
(56).
HRMS (ESI): m/z [M + H]+ calcd for C21H16N3OS+: 358.1009; found:
358.1011.
6-Phenyl-5-(1,3-thiazol-2-yl)imidazo[2,1-b][1,3]thiazole (3t)
Yellow solid; yield: 32.5 mg (57%); mp 127.9–128.6 °C.
IR (ATR): 2972, 1550, 1352, 1230, 1126, 1055, 967 cm–1
.
2-(2-Biphenyl-4-ylimidazo[1,2-a]pyridin-3-yl)-1,3-benzothiazole
(5d)
1H NMR (500 MHz, CDCl3): δ = 8.55 (d, J = 4.5 Hz, 1 H), 7.79 (d, J = 3.0
Hz, 1 H), 7.71–7.69 (m, 2 H), 7.50–7.41 (m, 3 H), 7.11 (d, J = 3.0 Hz, 1
H), 6.92 (d, J = 4.5 Hz, 1 H).
Yellow solid; yield: 45.3 mg (56%); mp 239.2–240.0 °C.
IR (ATR): 3059, 2962, 1538, 1509, 1120, 935, 829 cm–1
.
13C NMR (125 MHz, CDCl3): δ = 157.4, 151.2, 148.3, 142.2, 134.0,
129.6, 129.0, 128.7, 121.6, 118.8, 116.9, 112.4.
1H NMR (500 MHz, CDCl3): δ = 9.97 (d, J = 7.0 Hz, 1 H), 8.05 (d, J = 8.1
Hz, 1 H), 7.81–7.70 (m, 8 H), 7.48–7.36 (m, 5 H), 7.30 (t, J = 8.0 Hz, 1
H), 7.06 (t, J = 6.9 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 157.4, 152.8, 149.7, 146.3, 141.9,
140.4, 133.6, 132.4, 130.4, 128.7, 127.9, 127.5, 127.3, 127.2, 127.0,
126.0, 124.9, 122.3, 121.0, 117.1, 115.8, 113.7.
LRMS (EI, 70 eV): m/z (%) = 283 (57), 282 (100), 198 (6), 103 (5), 57
(5).
HRMS (ESI): m/z [M + H]+ calcd for C14H10N3S2+: 284.0311; found:
284.0316.
LRMS (EI, 70 eV): m/z (%) = 403 (81), 402 (100), 326 (6), 281 (7), 78
(7).
2-(2-Phenylimidazo[1,2-a]pyridin-3-yl)-1,3-benzothiazole (5a)
HRMS (ESI): m/z [M + H]+ calcd for C26H18N3S+: 404.1216; found:
Yellow solid; yield: 46.9 mg (72%); mp 162.2–163.1 °C.
404.1216.
IR (ATR): 3069, 2958, 1545, 1522 1292, 1090, 820 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 9.99 (d, J = 7.0 Hz, 1 H), 8.05 (d, J = 8.0
Hz, 1 H), 7.77–7.70 (m, 4 H), 7.53–7.50 (m, 3 H), 7.47–7.41 (m, 2 H),
7.31 (t, J = 7.5 Hz, 1 H), 7.07 (t, J = 6.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 157.7, 153.0, 150.5, 146.5, 133.8,
133.8, 130.2, 129.4, 128.7, 128.1, 127.4, 126.2, 125.0, 122.5, 121.1,
117.4, 116.1, 113.9.
2-[2-(4-Bromophenyl)imidazo[1,2-a]pyridin-3-yl]-1,3-benzothi-
azole (5e)
Brown solid; yield: 47.2 mg (58%); mp 228.5–229.6 °C.
IR (ATR): 3035, 2957, 1550, 1523, 1269, 1091, 1030, 826, 687 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 9.93 (d, J = 7.0 Hz, 1 H), 8.06 (d, J = 8.0
Hz, 1 H), 7.76– 7.74 (m, 2 H), 7.65–7.60 (m, 4 H), 7.50–7.42 (m, 2 H),
7.36–7.37 (m, 1 H), 7.10–7.07 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 156.9, 152.7, 148.6, 146.2, 133.5,
132.4, 131.7, 131.6, 127.8, 127.3, 126.1, 125.0, 123.7, 122.4, 121.0,
117.1, 115.8, 113.8.
LRMS (EI, 70 eV): m/z (%) = 327 (88), 326 (100), 253 (6), 163 (12), 73
(16).
HRMS (ESI): m/z [M + H]+ calcd for C20H14N3S+: 328.0903; found:
328.0905.
LRMS (EI, 70 eV): m/z (%) = 406 (75), 281 (55), 207 (100), 135 (23), 69
(12).
HRMS (ESI): m/z [M + H]+ calcd for C20H13BrN3S+: 406.0008; found:
406.0013.
2-[2-(4-Tolyl)imidazo[1,2-a]pyridin-3-yl]-1,3-benzothiazole (5b)
Yellow solid; yield: 46.3 mg (68%); mp 225.8–226.5 °C.
IR (ATR): 2978, 1540, 1515, 1269, 1198, 1072, 835 cm–1
.
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2-[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]-1,3-benzothi-
LRMS (EI, 70 eV): m/z (%) = 341 (81), 340 (100), 207 (6), 170 (11), 65
azole (5f)
(7).
HRMS (ESI): m/z [M + H]+ calcd for C21H16N3S+: 342.1059; found:
Yellow solid; yield: 50.5 mg (70%); mp 212.5–213.6 °C.
IR (ATR): 3120, 2962, 1539, 1509, 1373, 1215, 1093, 985, 718 cm–1
.
342.1059.
1H NMR (500 MHz, CDCl3): δ = 9.94 (d, J = 7.0 Hz, 1 H), 8.06 (d, J = 8.5
Hz, 1 H), 7.75 (d, J = 8.5 Hz, 2 H), 7.67 (d, J = 8.4 Hz, 2 H), 7.49–7.42 (m,
4 H), 7.34 (t, J = 7.5 Hz, 1 H), 7.08 (t, J = 7.0 Hz, 1 H).
2-(2-Methylimidazo[1,2-a]pyridin-3-yl)-1,3-benzothiazole (5j)
Yellow solid; yield: 30.7 mg (58%); mp 137.2–138.3 °C.
IR (ATR): 2926, 1557, 1540, 1510, 1349, 1235, 1031, 915 cm–1
.
13C NMR (125 MHz, CDCl3): δ = 156.9, 152.7, 148.6, 146.2, 135.3,
133.4, 132.0, 131.3, 128.7, 127.7, 127.3, 126.0, 124.9, 122.3, 120.9,
117.1, 115.8, 113.7.
1H NMR (500 MHz, CDCl3): δ = 10.08 (dd, J = 6.0, 1.0 Hz, 1 H), 8.04 (d,
J = 8.0 Hz, 1 H), 7.92–7.88 (m, 1 H), 7.66 (d, J = 8.5 Hz, 1 H), 7.51–7.48
(m, 1 H), 7.40–7.34 (m, 2 H), 7.05–7.02 (m, 1 H), 2.83 (s, 3 H).
LRMS (EI, 70 eV): m/z (%) = 361 (81), 360 (100), 281 (35), 253 (17),
13C NMR (125 MHz, CDCl3): δ = 157.3, 153.1, 147.8, 146.1, 133.3,
128.4, 127.1, 126.4, 124.7, 122.4, 121.1, 116.5, 113.6, 16.6.
163 (21).
HRMS (ESI): m/z [M + H]+ calcd for C20H13ClN3S+: 362.0513; found:
362.0518.
LRMS (EI, 70 eV): m/z (%) = 265 (80), 264 (100), 135 (7), 133 (7), 78
(17).
2-[2-(4-Fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-1,3-benzothi-
azole (5g)
HRMS (ESI): m/z [M + H]+ calcd for C15H12N3S+: 266.0746; found:
266.0749.
Yellow solid; yield: 38.8 mg (56%); mp 196.2–197.1 °C.
IR (ATR): 3052, 2957, 1539, 1350, 121, 1091, 979 cm–1
.
2-(2-Ethylimidazo[1,2-a]pyridin-3-yl)-1,3-benzothiazole (5k)
1H NMR (500 MHz, CDCl3): δ = 9.98 (d, J = 7.5 Hz, 1 H), 8.06 (d, J = 8.1
Hz, 1 H), 7.76–7.69 (m, 4 H), 7.49–7.43 (m, 2 H), 7.34 (t, J = 7.5 Hz, 1
H), 7.21 (t, J = 8.4 Hz, 2 H), 7.09 (t, J = 7.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 163.7 (d, JC–F = 247.3 Hz), 157.4, 152.9,
149.3, 146.4, 133.7, 132.1 (d, JC–F = 8.4 Hz), 129.9, 128.1, 127.4, 126.3,
125.1, 122.5, 121.1, 117.4, 116.1, 115.8 (d, JC–F = 21.6 Hz), 113.9.
Yellow solid; yield: 28.3 mg (51%); mp 140.9–141.7 °C.
IR (ATR): 3033, 2967, 1537, 1440, 1238, 1029, 910 cm–1
1H NMR (500 MHz, CDCl3): δ = 10.07 (d, J = 7.0 Hz, 1 H), 8.05 (d, J = 8.0
Hz, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.69 (d, J = 9.0 Hz, 1 H), 7.49 (t, J = 7.5
Hz, 1 H), 7.37 (q, J = 7.0 Hz, 2 H), 7.02 (t, J = 7.0 Hz, 1 H), 3.22 (q, J = 7.5
Hz, 2 H), 1.51 (t, J = 7.5 Hz, 3 H).
.
13C NMR (125 MHz, CDCl3): δ = 156.8, 152.9, 152.8, 146.0, 133.0,
128.1, 126.7, 126.1, 124.4, 122.2, 120.8, 116.4, 115.5, 113.21, 23.0,
12.9.
LRMS (EI, 70 eV): m/z (%) = 345 (73), 344 (100), 208 (9), 172 (15), 78
(11).
HRMS (ESI): m/z [M + H]+ calcd for C20H13FN3S+: 346.0809; found:
346.0813.
LRMS (EI, 70 eV): m/z (%) = 279 (100), 207 (18), 186 (10), 78 (22), 73
(11).
2-(7-Bethyl-2-phenylimidazo[1,2-a]pyridin-3-yl)benzo[d]thiazole
(5h)
HRMS (ESI): m/z [M + Na]+ calcd for C16H13N3NaS+: 302.0722; found:
302.0712.
Yellow solid; yield: 41.9 mg (61%); mp 188.3–189.5 °C.
IR (ATR): 3075, 2958, 1552, 1270, 1095, 836 cm–1
.
3-(1,3-Benzothiazol-2-yl)-2-phenylimidazo[1,2-a]pyrimidine (5l)
1H NMR (500 MHz, CDCl3): δ = 9.86 (d, J = 7.0 Hz, 1 H), 8.02 (d, J = 8.0
Hz, 1 H), 7.72–7.68 (m, 3 H), 7.51–7.42 (m, 5 H), 7.28 (t, J = 7.0 Hz, 1
H), 6.89 (d, J = 7.0 Hz, 1 H), 2.48 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 157.8, 153.0, 150.5, 147.0, 138.7,
134.0, 133.7, 130.2, 129.4, 128.7, 127.4, 126.1, 124.9, 122.4, 121.1,
116.4, 115.9, 115.7, 21.5.
Yellow solid; yield: 44.5 mg (68%); mp 232.3–233.1 °C.
IR (ATR): 3119, 2908, 1545, 1507, 1377, 1228, 933 cm–1
1H NMR (500 MHz, CDCl3): δ = 10.28 (dd, J = 7.0, 2.0 Hz, 1 H), 8.72 (dd,
J = 4.0, 2.0 Hz, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 7.77 (dd, J = 8.0, 2.0 Hz, 2
H), 7.71 (d, J = 7.8 Hz, 1 H), 7.57–7.50 (m, 3 H), 7.48–7.43 (m, 1 H),
7.37–7.29 (m, 1 H), 7.12 (dd, J = 7.0, 4.0 Hz, 1 H).
.
13C NMR (125 MHz, CDCl3): δ = 157.0, 152.6, 151.9, 151.6, 149.2,
136.0, 133.6, 133.1, 130.2, 129.8, 128.8, 126.4, 125.4, 122.6, 121.2,
114.5, 110.1.
LRMS (EI, 70 eV): m/z (%) = 341 (81), 340 (100), 207 (4), 170 (11), 65
(5).
HRMS (ESI): m/z [M + H]+ calcd for C21H16N3S+: 342.1059; found:
342.1065.
LRMS (EI, 70 eV): m/z (%) = 328 (85), 327 (100), 208 (8), 135 (7), 73
(28).
2-(6-Methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)-1,3-benzothi-
azole (5i)
HRMS (ESI): m/z [M + H]+ calcd for C19H13N4S+: 329.0855; found:
329.0863.
Yellow solid; yield: 42.5 mg (62%); mp 191.0–192.2 °C.
IR (ATR): 3073, 2961, 1543, 1513, 1271, 1089, 819 cm–1
.
Acknowledgment
1H NMR (500 MHz, CDCl3): δ = 9.73 (s, 1 H), 8.08 (d, J = 8.0 Hz, 1 H),
7.73–7.66 (m, 4 H), 7.52–7.46 (m, 4 H), 7.34–7.28 (m, 2 H), 2.48 (s, 3
H).
13C NMR (125 MHz, CDCl3): δ = 157.6, 152.7, 149.7, 145.2, 133.6,
130.2, 129.9, 129.0, 128.4, 125.8, 125.4, 124.7, 123.5, 122.2, 120.8,
116.3, 115.5, 18.4.
We gratefully acknowledge the NSFC (Nos. 21202121 and 21272178)
for financial support.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 687–696

696
X.-M. Ji et al.
Paper
Synthesis
Supporting Information
K.; Gunn-Moore, F.; Musilek, K. Curr. Med. Chem. 2015, 22, 730.
(c) Keri, R. S.; Patil, M. R.; Patil, S. A.; Budagumpi, S. Eur. J. Med.
Chem. 2015, 89, 207.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560395.
S
u
p
p
ortiInfogrmoaitn
S
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p
p
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(11) For reviews on benzothiazole-based materials, see: (a) Kang, E.;
Kim, K.; Kim, D.-E.; Shin, H.-K.; Lee, B.-J. Sci. Adv. Mater. 2014, 6,
2298. (b) Xiao, G. Y.; Wang, Y.; Chi, H. J.; Lu, Y. H.; Xu, Y. Q.; Hu, J.
Y.; Hu, Z. Z.; Sun, Q. B. Adv. Mater. Res. 2014, 1033–1034, 342;
DOI: 10.4028/www.scientific.net/AMR.1033-1034.342.
References
(1) (a) Enguehard-Gueiffier, C.; Gueiffier, A. Mini-Rev. Med. Chem.
2007, 7, 888. (b) Couty, F.; Evano, G. In Comprehensive Heterocy-
clic Chemistry III; Vol.11; Katritzky, A. R.; Ramsden, C. A.;
Scriven, E. F. V.; Taylor, R. J. K., Eds.; Elsevier Science: Oxford,
2008, Chap 11.10; 409, and references therein.
(2) (a) Barradas, J. S.; Errea, M. I.; D’Accorso, N. B.; Sepúlveda, C. S.;
Damonte, E. B. Eur. J. Med. Chem. 2010, 46, 259. (b) Juspin, T.;
Laget, M.; Terme, T.; Azas, N.; Vanelle, P. Eur. J. Med. Chem. 2010,
45, 840.
(3) Ali, A.; Cablewski, T.; Francis, C. L.; Ganguly, A. K.; Sargent, R. M.;
Sawutz, D. G.; Winzenberg, K. N. Bioorg. Med. Chem. Lett. 2011,
21, 4160.
(4) For selected references, see: (a) Park, J.-H.; El-Gamal, M. I.; Lee,
Y. S.; Oh, C.-H. Eur. J. Med. Chem. 2011, 46, 5769. (b) Ali, A. R.; El-
Bendary, E. R.; Ghaly, M. A.; Shehata, I. A. Eur. J. Med. Chem.
2014, 75, 492.
(c) Ambrico, M.; Della Vecchia, N. F.; Ambrico, P. F.; Cardone, A.;
Cicco, S. R.; Ligonzo, T.; Avolio, R.; Napolitano, A.; d’Ischia, M.
Adv. Funct. Mater. 2014, 24, 7161. (d) Conceição, D. S.; Ferreira,
D. P.; Graça, V. C.; Silva, C. R.; Santos, P. F.; Vieira Ferreira, L. F.
Tetrahedron 2015, 71, 967.
(12) For selected references on metal-catalyzed C–H activation of
benzothiazoles, see: (a) Wu, X.-F.; Anbarasan, P.; Neumann, H.;
Beller, M. Angew. Chem. Int. Ed. 2010, 49, 7316. (b) Ranjit, S.; Lee,
R.; Heryadi, D.; Shen, C.; Wu, J.-E.; Zhang, P.; Huang, K.-W.; Liu,
X. J. Org. Chem. 2011, 76, 8999. (c) Chu, L.; Qing, F.-L. J. Am.
Chem. Soc. 2012, 134, 1298. (d) Yu, D.; Lu, L.; Shen, Q. Org. Lett.
2013, 15, 940. (e) Zhao, W.-M.; Chen, X.-L.; Yuan, J.-W.; Qu, L.-
B.; Duan, L.-K.; Zhao, Y.-F. Chem. Commun. 2014, 50, 2018.
(f) Zhu, F.; Wang, Z.-X. Org. Lett. 2015, 17, 1601.
(13) For selected references on C–H functionalization of benzothi-
azoles by a free-radical procedure, see: (a) He, T.; Yu, L.; Zhang,
L.; Wang, L.; Wang, M. Org. Lett. 2011, 13, 5016. (b) Wang, J.;
Wang, S.; Wang, G.; Zhang, J.; Yu, X.-Q. Chem. Commun. 2012,
48, 11769. (c) Xie, Z.; Cai, Y.; Hu, H.; Lin, C.; Jiang, J.; Chen, Z.;
Wang, L.; Pan, Y. Org. Lett. 2013, 15, 4600. (d) Liu, Y.; Jiang, B.;
Zhang, W.; Xu, Z. J. Org. Chem. 2013, 78, 966. (e) Chen, X.-L.; Li,
X.; Qu, L.-B.; Tang, Y.-C.; Mai, W.-P.; Wei, D.-H.; Bi, W.-Z.; Duan,
L.-K.; Sun, K.; Chen, J.-Y.; Ke, D.-D.; Zhao, Y.-F. J. Org. Chem.
2014, 79, 8407.
(5) Budriesi, R.; Ioan, P.; Leoni, A.; Pedemonte, N.; Locatelli, A.;
Micucci, M.; Chiarini, A.; Galietta, L. J. V. J. Med. Chem. 2011, 54,
3885.
(6) (a) Shao, N.; Pang, G.-X.; Yan, C.-X.; Shi, G.-F.; Cheng, Y. J. Org.
Chem. 2011, 76, 7458. (b) Stasyuk, A. J.; Banasiewicz, M.;
Cyrański, M. K.; Gryko, D. T. J. Org. Chem. 2012, 77, 5552.
(7) For references on imidazo[2,1-b]thiazoles, see: (a) Kolavi, G.;
Hegde, V.; Khazi, A. I. Tetrahedron Lett. 2006, 47, 2811.
(b) Huang, G.; Sun, H.; Qiu, X.; Jin, C.; Lin, C.; Shen, Y.; Jiang, J.;
Wang, L. Org. Lett. 2011, 13, 5224. (c) Mukherjee, C.; Watanabe,
K. T.; Biehl, E. R. Tetrahedron Lett. 2012, 53, 6008.
(14) Anastas, P. T. W.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford University Press: Oxford, 1998.
(15) (a) Lee, Y. M.; Moon, M. E.; Vajpayee, V.; Filimonov, V. D.; Chi,
K.-W. Tetrahedron 2010, 66, 7418. (b) Bayarmagnai, B.; Matheis,
C.; Risto, E.; Goossen, J. L. Adv. Synth. Catal. 2014, 356, 2343.
(16) For selected references, see: (a) Mo, F.; Jiang, Y.; Qiu, D.; Zhang,
Y.; Wang, J. Angew. Chem. Int. Ed. 2010, 49, 1846. (b) Fabrizi, G.;
Goggiamani, A.; Sferrazza, A.; Cacchi, S. Angew. Chem. Int. Ed.
2010, 49, 4067. (c) Wu, X.-F.; Neumann, H.; Beller, M. Angew.
Chem. Int. Ed. 2011, 50, 11142. (d) Le Callonnec, F.; Fouquet, E.;
Felpin, F.-X. Org. Lett. 2011, 13, 2646. (e) Qiu, D.; Meng, H.; Jin,
L.; Wang, S.; Tang, S.; Wang, X.; Mo, F.; Zhang, Y.; Wang, J.
Angew. Chem. Int. Ed. 2013, 52, 11581. (f) Wang, X.; Xu, Y.; Mo,
F.; Ji, G.; Qiu, D.; Feng, J.; Ye, Y.; Zhang, S.; Zhang, Y.; Wang, J.
J. Am. Chem. Soc. 2013, 135, 10330. (g) Wang, X.; Cuny, G.; Noël,
T. Angew. Chem. Int. Ed. 2013, 52, 7860. (h) Xia, Z.; Huang, J.; He,
Y.; Zhao, J.; Lei, J.; Zhu, Q. Org. Lett. 2014, 16, 2546.
(17) For selected references on the Meerwein arylation, see:
(a) Heinrich, M. R. Chem. Eur. J. 2009, 15, 820. (b) Hari, D. P.;
König, B. Angew. Chem. Int. Ed. 2013, 52, 4734. (c) Hari, D. P.;
Schroll, P.; König, B. J. Am. Chem. Soc. 2012, 134, 2958.
(d) Honraedt, A.; Raux, M.-A.; Le Grognec, E.; Jacquemin, D.;
Felpin, F.-X. Chem. Commun. 2014, 50, 5236. (e) Crisóstomo, F.
P.; Martín, T.; Carrillo, R. Angew. Chem. Int. Ed. 2014, 53, 2181.
(8) For reviews on functionalization of imidazo[1,2-a]pyridines,
see: Koubachi, J.; El Kazzouli, S.; Bousmina, M.; Guillaumet, G.
Eur. J. Org. Chem. 2014, 5119; and references cited therein.
(9) For selected references on C–H arylation of imidazoheterocy-
cles, see: (a) Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.;
Mouaddib, A.; Guillaumet, G. Synlett 2006, 3237. (b) Touré, B. B.;
Lane, B. S.; Sames, D. Org. Lett. 2006, 8, 1979. (c) Aginagalde, M.;
Vara, Y.; Arrieta, A.; Zangi, R. V.; Cebolla, L.; Delgado-Camón, A.;
Cossio, F. P. J. Org. Chem. 2010, 75, 2776. (d) Cao, H.; Zhan, H.;
Lin, Y.; Lin, X.-L.; Du, Z.; Jiang, H. Org. Lett. 2012, 14, 1688. (e) Fu,
H. Y.; Chen, L.; Doucet, H. J. Org. Chem. 2012, 77, 4473. (f) Lee, J.;
Chung, J.; Byun, S. M.; Kim, B. M.; Lee, C. Tetrahedron 2013, 69,
5660. (g) Ke, C.-H.; Kuo, B.-C.; Nandi, D.; Lee, H. M. Organome-
tallics 2013, 32, 4775. (h) Wang, S.; Liu, W.; Cen, J.; Liao, J.;
Huang, J.; Zhan, H. Tetrahedron Lett. 2014, 55, 1589. (i) Zhao, L.;
Zhan, H.; Liao, J.; Huang, J.; Chen, Q.; Qiu, H.; Cao, H. Catal.
Commun. 2014, 56, 65. (j) Huang, S.; Qing, J.; Wang, S.; Wang,
H.; Zhang, L.; Tang, Y. Org. Biomol. Chem. 2014, 12, 2344.
(10) For reviews on benzothiazole-based drugs, see: (a) Raju, G. N.;
Sai, K. B.; Chandana, K.; Rao, N. R. J. Chem. Pharm. Res. 2015,
7(4), 286. (b) Hroch, L.; Aitken, L.; Benek, O.; Dolezal, M.; Kuca,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 687–696