SNAr versus Buchwald-Hartwig Amination/Amidation in the Imidazo[2,1-b][1,3,4]thiadiazole Series

Article abstract of DOI:10.1002/ejoc.201500977

An original and efficient palladium-catalyzed amination of imidazo[2,1-b][1,3,4]thiadiazole is reported. The S_NAr and Buchwald-Hartwig cross-coupling reactions were investigated to access C-2 aminated imidazo[1,2-b][1,3,4]thiadiazole derivatives. The reaction conditions were optimized under microwave irradiation, and a wide range of amines were used to determine the scope and limitations of the method. To complete this study, the palladium-catalyzed and S_NAr amination reactions were compared to determine the best strategy. The X-ray crystallographic data of imidazo[2,1-b][1,3,4]thiadiazole derivative 20 was used to formally establish the structures of the products. An efficient and convenient method has been developed for the preparation of C-2 aminated imidazo[1,2-b][1,3,4]thiadiazole derivatives by using S_NAr or Buchwald-Hartwig reactions. The process was highly compatible with various functional groups and afforded the final compounds in very good yields.

Full text of DOI:10.1002/ejoc.201500977

FULL PAPER
DOI: 10.1002/ejoc.201500977
S Ar versus Buchwald–Hartwig Amination/Amidation in the
N
Imidazo[2,1-b][1,3,4]thiadiazole Series
[a]
[b]
[b]
[b]
Chloé Copin, Stéphane Massip, Jean-Michel Léger, Christian Jarry,
[a]
[a]
Frédéric Buron, and Sylvain Routier*
Keywords: Synthetic methods / Nucleophilic substitution / Cross-coupling / Palladium / Amination / Nitrogen heterocycles
An original and efficient palladium-catalyzed amination of
imidazo[2,1-b][1,3,4]thiadiazole is reported. The S Ar and
were used to determine the scope and limitations of the
method. To complete this study, the palladium-catalyzed and
N
Buchwald–Hartwig cross-coupling reactions were investi-
gated to access C-2 aminated imidazo[1,2-b][1,3,4]thiadi-
azole derivatives. The reaction conditions were optimized
under microwave irradiation, and a wide range of amines
N
S Ar amination reactions were compared to determine the
best strategy. The X-ray crystallographic data of imidazo[2,1-
b][1,3,4]thiadiazole derivative 20 was used to formally estab-
lish the structures of the products.
Introduction
pounds would be attainable. To this end, after previously
preparing a library of type I derivatives, we successfully ex-
plored their reactivity toward Suzuki–Miyaura cross-cou-
pling reactions at the C-2 position and reported these un-
precedented 2,6-disubstituted imidazo[2,1-b][1,3,4]thiadi-
Imidazo[1,2-b][1,3,4]thiadiazoles have been used exten-
sively over the last 10 years in the design of bioactive com-
[
1]
pounds. This heterocycle is found in compounds that have
a wide range of promising biological properties such as an-
[28]
azole derivatives.
[
2]
[3]
[4]
titumor, antitubercular, and analgesic characteristics.
As amino(het)Ar groups are highly valuable for pharma-
ceutical applications, a new challenge was to develop a
method that gives access to C-2 aminated derivatives and
determine the potency of the release of the C-2 bromine
atom under amination conditions. Herein, we report our
progress and an efficient route to access a library of 2-ami-
noimidazo[2,1-b][1,3,4]thiadiazole derivatives II by em-
Thus, chemists have been actively pursuing methods for the
selective functionalization of the imidazo[2,1-b][1,3,4]thia-
diazole core.
Current strategies for the preparation of substituted im-
idazo[1,2-b][1,3,4]thiadiazole derivatives generally involve
building the fused aromatic heterocycle by condensation of
2-amino-5-substituted-[1,3,4]thiadiazoles with various α-
ploying S Ar or Buchwald–Hartwig cross-coupling reac-
N
[5–13]
haloketones or acetophenones.
vantage of forming the two fused rings with the desired sub-
stituents in the appropriate positions within a limited
This route has the ad-
tions (Figure 1).
[
14–27]
number of steps.
A major drawback, however, is the
need for strongly acidic conditions, which severely restrict
its compatibility. Additionally, the unavailability of starting
materials and their complex preparations decrease the at- Figure 1. C-2 amination program (R , R = H, CO, alkyl, aryl,
1 2
benzyl; R = H, phenyl, pyridinyl, ester, Me).
tractiveness of using the imidazo[2,1-b][1,3,4]thiadiazole
core in large chemistry or medicinal chemistry programs.
Our major interest in the field is to develop an efficient
synthesis for the imidazo[2,1-b][1,3,4]thiadiazole scaffold,
which would then allow its subsequent functionalization,
as only a few methods in this area are currently available.
Results and Discussion
Versatile methods capable of furnishing a library of 2-
Subsequently, innovative and biologically active com- aminated imidazo[1,2-b][1,3,4]thiadiazole derivatives need
to be compatibile with a wide range of amines, regardless
of their nucleophilic properties. The reactivity of the C-2
[
[
a] University of Orléans, CNRS, ICOA, UMR 7311,
45067 Orléans, France
position was first examined under S Ar conditions by treat-
N
E-mail: sylvain.routier@univ-orléans.fr
http://www.univ-orleans.fr/
b] Université de Bordeaux, Pharmacochimie, FRE CNRS 3396,
ing
diazole (1) with morpholine. Under the reported conditions
Table 1), which use an excess amount of morpholine in a
solvent, the desired product 2 was obtained in very low
2-bromo-6-(4-nitrophenyl)imidazo[1,2-b][1,3,4]thia-
1
36 Rue Léo Saignat, 33076 Bordeaux Cedex, France
(
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500977
6932
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6932–6942

S
N
Ar versus Buchwald–Hartwig Amination/Amidation
Table 1. Optimization of S Ar conditions to synthesize 2.
N
rolactam (Table 3). First, we used Pd(OAc) as the palla-
2
dium source in the presence of racemic 2,2Ј-bis(diphenyl-
phosphino)-1,1Ј-binaphthyl (rac-BINAP) as the bidentate
ligand, Cs CO as the base, and dioxane as the solvent.
2
3
However, only starting material was recovered (Table 3, En-
try 1). When the phosphine ligand was replaced by 4,5-
bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos),
the desired compound 14 was obtained in a low 6% yield.
Notably, the starting material was completely consumed
(Table 3, Entry 2), which indicates the degradation of the
reaction mixture rather than a lack of reactivity. With
Pd dba (dba = dibenzylideneacetone) as the palladium cat-
2
3
alyst, the yield increased to 40%, and with a fine adjust-
ment of the temperature (at 130 °C), the reaction afforded
the desired product in 91% yield (Table 3, Entry 4).
Changing the nature of the base indicated that using
Entry Equiv. Solvent
Temperature
Time
h]
% Yield
2
[a]
[
1
2
3
4
10.0 CH
2
Cl
2
reflux
reflux
10
10
10
1
trace
11
83
2.0
–
iPrOH
morpholine 100 °C
morpholine 150 °C, MW
K CO further improved the results to an excellent 98%
2 3
–
90
yield (Table 3, Entry 5) along with a significant reduction
of the reaction time to 15 min. Decreasing the quantities of
the metal source to 10%, the ligand to 10%, and the base
to 2.0 equiv. were tolerated without any change to the effi-
ciency of the reaction (Table 3, Entry 6), but modifying the
nature of the solvent (to toluene or DME) drastically de-
[a] Yields of isolated compounds are provided.
yield.[29–31] Although the insolubility of starting material 1 creased the yield (Table 3, Entries 7 and 8). To show that
was detrimental to the classical addition/elimination cas- the amination follows a palladium-assisted mechanism
cade reaction (Table 1, Entries 1 and 2), the yield could be without a concomitant S Ar reaction, we carried out the
N
enhanced by performing the reaction without a solvent. transformation without the catalyst (Table 3, Entry 9) and,
This assay afforded compound 2 in 83% yield (Table 1, En- as expected, no reaction occurred.
try 3). The best results were obtained, however, by replacing
the thermal activation mode with microwave irradiation method, we next used our library of 6-substituted 2-bromo-
MW), which afforded derivative 2 in a very satisfactory imidazo[2,1-b][1,3,4]thiadiazole derivatives (Table 4) in the
To explore the scope and limitations of the Pd-coupling
(
9
0% yield (Table 1, Entry 4).[
32]
reaction with δ-valerolactam. The reactions proceeded ef-
After the direct condensation of a secondary aliphatic ficiently regardless of the functional group (i.e., phenyl,
amine with 2-bromo-imidazothiadiazole 1 was successfully phenyl with electron-withdrawing or electron-donating sub-
accomplished, we explored the scope of this method by tre- stituent, or alkyl) at the C-6 position. The success of the
ating a library of previously prepared 2-bromo-6-(het)aryl- reaction was limited when basic sensitive functionalities
imidazo[1,2-b][1,3,4]thiadiazole derivatives with various ni- such as phenol or esters were used, as compounds 22 and
trogen-containing compounds. Both linear and cyclic ali- 24 were isolated in only 43 and 45% yield, respectively
phatic amines led to imidazo[2,1-b][1,3,4]thiadiazol- (Table 4), Entries 10 and 12). The same behavior occurred
2-yl-substituted amines 2–12 (Table 2) in fairly good yields with poorly soluble starting materials. For example, starting
regardless of the nature of the (het)Ar moiety at C-6 [(het)- with an imidazo[1,2-b][1,3,4]thiadiazole derivative with a 4-
Ar = phenyl, aryls with an electron-withdrawing or elec- methoxyphenyl or 4-pyridinyl substituent in C-6 resulted in
tron-donating group, or pyridinyl]. Reactions with highly either a low yield or no reactivity (Table 4, Entries 2 and
nucleophilic cyclic secondary amines (Table 2, Entries 1, 5, 11).
8
–11) were more efficient than those conducted with
aliphatic amines or benzylamines (Table 2, Entries 3, 4, 6, of the amine starting material (Table 5). The reaction with
and 7).
2-pyrrolidinone gave the desired product 26 in low yield
To complete this study, we then evaluated the influence
During this first stage of our investigation, we encoun- (Table 5, Entry 2), whereas using aniline afforded product
tered two limitations, that is, when aniline or a lactam was 27 in an excellent isolated yield of 96% (Table 5, Entry 3).
used as the nitrogen derivative, the final compounds (i.e., The same behavior was observed with other aromatic amine
13 and 14, Table 2, Entries 12 and 13) were never detected. derivatives. Regardless of the functional groups present or
To access these derivatives, it became necessary to develop their positions (i.e., electron-donating or electron-with-
a Pd-catalyzed C–N bond-forming strategy, which was an drawing groups), the efficiency of this reaction remained
[33–47]
attractive alternative to the S Ar method.
very high. Factors such as steric hindrance, the presence of
N
To avoid any competition from a substitution reaction as acidic hydrogen atoms, and electronic effects did not alter
a result of a nucleophilic attack at C-2 of the imidazothiadi- the efficiency of the cross-coupling reaction, as products
azole derivative by a secondary amine,[ we decided to op- 28–31 were isolated in high yields (81–96%, Table 5, En-
timize the Buchwald–Hartwig reaction by using δ-vale- tries 4–7).
48]
Eur. J. Org. Chem. 2015, 6932–6942
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6933

C. Copin, S. Massip, J.-M. Léger, C. Jarry, F. Buron, S. Routier
Table 2. Synthesis of imidazo[2,1-b][1,3,4]thiadiazol-2-yl-substituted amines 2–14.
FULL PAPER
[a] Yields of isolated compounds are provided. [b] n.d.: not detected. Starting material was fully recovered.
The sole limitation in this trend involved the use of 3-
Finally, a single crystal of 20 was used for X-ray structure
aminopyridine, which inhibited the reactivity. The efficiency analysis (Figure 2). A thin crystal (0.20ϫ0.10ϫ0.05 mm)
of the reaction was partially restored, however, by im- was collected at 253 K to establish its three-dimensional ar-
proving the reactivity of the pyridine with the addition of a rangement. The crystal structure presents a classical disor-
methoxy group (i.e., 3-amino-6-methoxypyridine). In this dered CF group.
3
case, 33 was obtained in a 58% yield (Table 5, Entries 8
The crystalline cohesion of 20 is ensured in two ways.
and 9). To determine whether the aniline moiety can be The first involves a weak hydrogen bond (dO–H = 2.17 Å)
introduced into other 6-arylated imidazo[2,1-b][1,3,4]thiadi- along the b axis, and the second involves a head-to-tail
azoles, we performed two final experiments, which fortu- stacking between the imidazothiadazole cores (around
nately led to the expected products in near quantitative 3.40 Å), which are approximately parallel to the (101)
yields (Table 5, Entries 10 and 11).
plane.
6934
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6932–6942

S
N
Ar versus Buchwald–Hartwig Amination/Amidation
Table 3. Optimization of the conditions for the formation of 14.
Entry
Catalyst [equiv.]
Ligand [equiv.]
Base [equiv.]
Solvent
Temp, Time
% Yield 14[a]
1
2
3
4
5
6
7
8
9
Pd(OAc)
Pd(OAc)
2
2
(0.1)
(0.1)
(0.1)
(0.1)
(0.1)
(0.05)
(0.05)
(0.05)
rac-Binap (0.2)
Xantphos (0.2)
Xantphos (0.2)
Xantphos (0.2)
Xantphos (0.2)
Xantphos (0.1)
Xantphos (0.1)
Xantphos (0.1)
Xantphos (0.1)
Cs
Cs
Cs
Cs
2
2
2
2
CO
CO
CO
CO
3
3
3
3
(3.0)
(3.0)
(3.0)
(3.0)
(3.0)
(2.0)
(2.0)
(2.0)
(2.0)
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
DME[
MW, 150 °C, 1 h
MW, 150 °C, 1 h
MW, 150 °C, 1 h
MW, 130 °C, 1 h
MW, 130 °C, 15 min
MW, 130 °C, 15 min
MW, 130 °C, 15 min
MW, 130 °C, 15 min
MW, 130 °C, 15 min
–
6
Pd
2
Pd
2
Pd
2
Pd
2
Pd
2
Pd
2
–
dba
dba
dba
dba
dba
dba
3
3
3
3
3
3
40
91
98
97
39
81
n.d.[
K
K
K
K
K
2
2
2
2
2
CO
CO
CO
CO
CO
3
3
3
3
3
b]
c]
dioxane
[a] Yields of isolated compounds are provided. [b] DME = 1,2-dimethoxyethane. [c] n.d.: not detected. The starting material was fully
recovered.
Table 4. Scope of reaction between 2-bromo-6-substituted-imidazo[2,1-b][1,3,4]thiadiazoles and δ-valerolactam – synthesis of 14–25.
1
[
a] Yields of isolated compounds are provided. [b] Detected by H NMR spectroscopy.
Eur. J. Org. Chem. 2015, 6932–6942
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6935

C. Copin, S. Massip, J.-M. Léger, C. Jarry, F. Buron, S. Routier
FULL PAPER
Table 5. Limitations of the amine.
[a] Yields of isolated compounds are provided. [b] n.d.: not detected. Starting material was fully recovered.
groups at the C-2 position of the imidazo[2,1-b][1,3,4]-
thiadiazole series. S Ar reactions could only be performed
N
with highly nucleophilic amines, but Buchwald–Hartwig
cross-coupling reactions in combination with microwave ir-
radiation could be used to overcome the inefficiency of po-
orly nucleophilic amines. In addition, the nature and posi-
tion of additional substituents on the imidazothiadiazole
core can greatly influence the efficiency of the reaction.
These new synthetic routes will undoubtedly have a major
impact on the synthesis of new bioactive compounds that
contain the rare imidazothiadiazole scaffold as the central
Figure 2. X-ray crystal structure of 20.
Conclusions
This study provides chemists an overview of methods skeleton. Efforts to achieve these objectives are currently in
and conditions that can be employed to introduce aminated progress.
6936
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6932–6942

N
S Ar versus Buchwald–Hartwig Amination/Amidation
2
-(Morpholin-4-yl)-6-(4-nitrophenyl)imidazo[2,1-b][1,3,4]thiadi-
Experimental Section
azole (2): The reaction was carried out as described in general pro-
cedure A1 by using 1 (500 mg, 1.54 mmol, 1.0 equiv.) in morph-
oline (8 mL) to afford 2 (459 mg, 90 %) as a yellow solid; m.p.
General Methods: All reagents were purchased from commercial
suppliers and used without further purification. Microwave-assisted
reactions were carried out with a microwave instrument, and an IR
sensor was used to measure the temperature of the reaction mix-
tures. The progress of the each reaction was monitored by thin
layer chromatography (TLC). Compounds were visualized by UV
irradiation. Flash column chromatography was performed on silica
gel 60 (230–400 mesh, 0.040–0.063 mm). Melting points (°C) were
1
Ͼ260 °C. R
400 MHz, CDCl
J = 8.7 Hz, 2 H, 2 Har), 7.88 (s, 1 H, 5-H), 3.93–3.80 [m, 4 H, 2
f
= 0.65 (petroleum ether/EtOAc, 1:9). H NMR
(
3
): δ = 8.24 (d, J = 8.7 Hz, 2 H, 2 Har), 7.90 (d,
13
CH
CDCl
), 124.9 (2 CHar), 124.4 (2 CHar), 111.3 (C-5), 66.0 [2 CH
8.5 [2 CH (O)] ppm. IR [attenuated total reflectance (ATR) dia-
mond]: ν˜ = 1597, 1560, 1530, 1499, 1450, 1328, 1272, 1235, 1071,
2
(N)], 3.55–3.43 [m, 4 H, 2 CH
2
(O)] ppm. C NMR (101 MHz,
), 142.6 (C ), 141.5 (C ), 140.8
(N)],
3
): δ = 165.4 (C ), 146.5 (C
q
q
q
q
(
C
q
2
1
13
recorded with the samples in open capillary tubes. The H and
C
4
2
NMR spectroscopic data were recorded with a spectrometer at 250
and 62.9 MHz, respectively, or a spectrometer at 400 and 100 MHz,
respectively. Chemical shifts are reported in parts per million from
tetramethylsilane as the internal standard. The following abbrevi-
ations are used to describe the multiplicity of the proton signals:
s (singlet), d (doublet), t (triplet), q (quartet), qt (quintuplet), m
– 1
1
033, 905, 849, 737, 697 cm . HRMS (ESI): calcd. for
S [M + H]+ 332.08119; found 332.08139.
14 13 5 3
C H N O
2-(Morpholin-4-yl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazole (3): The
reaction was carried out as described in general procedure A1 by
using the corresponding bromo derivative (400 mg, 1.44 mmol,
(multiplet). Coupling constants are reported in Hertz. High resolu-
1.0 equiv.) in morpholine (5 mL) to afford 3 (400 mg, 87%) as a
tion mass spectrometry was performed on a Q-TOF mass spec-
trometer.
white solid; m.p. 212–214 °C. R
7
f
= 0.21 (petroleum ether/EtOAc,
): δ = 7.77 (d, J = 7.5 Hz, 2 H, 2
1
:3). H NMR (400 MHz, CDCl
3
X-ray Crystallography of Compound 20: The crystallographic data
of compound 20 were collected at 253 K by using an R-Axis Rapid
Rigaku MSC diffractometer with monochromatic Cu-K
H
ar), 7.75 (s, 1 H, 5-H), 7.38 (t, J = 7.5 Hz, 2 H, 2 Har), 7.24 (m,
H, Har), 3.95–3.73 [m, 4 H, 2 CH (N)], 3.58–3.35 [m, 4 H, 2
(O)] ppm. 1 C NMR (101 MHz, CDCl
): δ = 165.0 (C ), 143.9
), 141.4 (C ), 134.4 (C ), 128.8 (2 CHar), 127.1 (CHar), 124.8 (2
CHar), 109.2 (C-5), 66.0 [2 CH (N)], 48.5 [2 CH (O)] ppm. IR
ATR diamond): ν˜ = 3408, 2967, 2869, 1551, 1531, 1476, 1444,
1
CH
2
α
radiation
3
2
3
q
(λ = 1.54187 Å) and a curved image plate detector. The unit cell
(
C
q
q
q
determination and data reduction were performed by using the
Crystal Clear program suite[ on the full set of data. The structure
was solved by direct methods and refined by using the Shelx 97
49]
2
2
(
–
1
1323, 1267, 1239, 1116, 1071, 1037, 940, 903, 780, 717, 701 cm .
suite of programs in the integrated WinGX system.[51] The posi-
tions of the H atoms were deduced from the coordinates of the
non-H atoms and confirmed by Fourier synthesis. The non-H
atoms were refined with anisotropic temperature parameters. The
H atoms were included for structure-factor calculations, but they
were not refined. The PLATON[ program was used for analysis
[50]
HRMS (ESI): calcd. for C14
2
14 4
H N
OS [M + H]+ 287.09611; found
87.09641.
2-(Benzylamino)-6-phenylimidazo[2,1-b][1,3,4]thiadiazole (4): The
reaction was carried out as described in general procedure A2 by
using the corresponding bromo derivative (100 mg, 0.36 mmol,
52]
and drawing figures with thermal ellipsoids at a 50% probability 1.0 equiv.) in benzylamine (2 mL). The crude product was purified
level.
by flash chromatography on silica gel (petroleum ether/EtOAc, 5:5)
to afford 4 (75 mg, 69%) as a beige solid; m.p. 174–176 °C. R
f
=
CCDC-1405180 (for 20) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
1
0.24 (petroleum ether/EtOAc, 7:3). H NMR (400 MHz, CDCl
3
):
δ = 7.79–7.67 (m, 3 H, 5-H + 2 Har), 7.43–7.29 (m, 7 H, 7 Har),
7
5
.25 (m, 1 H, Har), 5.66 (t, J = 5.1 Hz, 1 H, NH), 4.53 (d, J =
1
3
.1 Hz, 2 H, CH
2
) ppm. C NMR (101 MHz, CDCl
3
): δ = 162.0
General Procedure A. Nucleophilic Substitution
(
C
q
), 143.79 (C ), 141.1 (C
q
q
), 136.9 (C ), 134.4 (C ), 129.0 (2 CHar),
q
q
Procedure A1: A mixture of the 2-bromoimidazo[2,1-b][1,3,4]- 128.8 (2 CH ), 128.2 (CH ), 128.0 (2 CH ), 127.1 (CH ), 124.8
ar
ar
ar
ar
thiadiazole derivative (1.0 equiv.) in an excess amount of the amine
ar 2
(2 CH ), 109.5 (C-5), 49.0 (CH ) ppm. IR (ATR diamond): ν˜ =
(
3 mL for 150 mg) was heated at 150 °C for 60 min under micro-
3229, 3027, 1562, 1532, 1467, 1451, 1436, 1351, 1255, 1234, 1023,
–
1
wave irradiation. The reaction mixture was then poured into water.
After stirring at room temperature for 30 min, the suspension was
filtered, and the filter cake was rinsed with water. The desired com-
pound was then oven-dried.
17 14 4
771, 714, 700, 692 cm . HRMS (ESI): calcd. for C H N S [M +
+
H] 307.10119; found 307.10143.
2-(Butylamino)-6-phenylimidazo[2,1-b][1,3,4]thiadiazole (5): The re-
action was carried out as described in general procedure A2 by
using the corresponding bromo derivative (100 mg, 0.36 mmol,
Procedure A2: A mixture of the 2-bromoimidazo[2,1-b][1,3,4]-
thiadiazole derivative (1.0 equiv.) in an excess amount of the amine
1
.0 equiv.) in n-butylamine (2 mL). The crude product was purified
by flash chromatography on silica gel (petroleum ether/EtOAc, 7:3)
to afford 5 (77 mg, 79%) as a white solid; m.p. 158–160 °C. R
(3 mL for 150 mg) was heated at 150 °C for 60 min under micro-
wave irradiation. The reaction mixture was then diluted with
dichloromethane and purified by flash chromatography on a silica
gel column.
f
=
1
0
3
.27 (petroleum ether/EtOAc, 7:3). H NMR (250 MHz, CDCl ):
δ = 7.80–7.70 (m, 3 H, 5-H + 2 Har), 7.44–7.33 (m, 2 H, 2 Har),
7.26–7.18 (m, 1 H, Har), 4.93 (t, J = 5.7 Hz, 1 H, NH), 3.37 (td, J
General Procedure B. Buchwald–Hartwig Coupling: A solution of
the 2-bromoimidazo[2,1-b][1,3,4]thiadiazole derivative (1.0 equiv.),
potassium carbonate (2.0 equiv.), and the amine (1.5 equiv.) in dry
= 7.1, 5.7 Hz, 2 H, NHCH
NHCH CH CH CH ), 1.52–1.33 (m, 2 H, NHCH
0.96 (t, J = 7.3 Hz, 3 H, NHCH CH CH CH ) ppm. C NMR
(101 MHz, CDCl ): δ = 162.5 (C ), 143.6 (C ), 141.2 (C ), 134.5
(C ), 128.8 (2 CHar), 127.0 (CHar), 124.8 (2 CHar), 109.4 (C-5),
44.9 (NHCH
(NHCH CH
2
CH
2
CH
2
CH
3
), 1.65 (p, J = 7.1 Hz, 2 H,
2
2
2
3
2
CH CH CH ),
2
1
2
3
3
1
,4-dioxane (4 mL for 100 mg) was degassed by bubbling argon
through the mixture for 15 min. Xantphos (0.1 equiv.) and Pd dba
0.05 equiv.) were then added, and the mixture was heated at 130 °C
2
2
2
3
2
3
3
q
q
q
(
q
for 15 min under microwave irradiation. The reaction mixture was
then diluted with dichloromethane and purified by flash
chromatography on a silica gel column.
2
CH
CH
2
CH
CH
2
3
CH
3
), 31.3 (NHCH
CH
2
CH
CH
2
CH
CH
2
CH
3
), 20.1
2
2
2
), 13.8 (NHCH
2
2
2
3
) ppm. IR
(ATR diamond): ν˜ = 3215, 2926, 2868, 1570, 1535, 1463, 1439,
Eur. J. Org. Chem. 2015, 6932–6942
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6937

C. Copin, S. Massip, J.-M. Léger, C. Jarry, F. Buron, S. Routier
FULL PAPER
–1
1
+
237, 768, 718, 693 cm . HRMS (ESI): calcd. for C14
H] 273.11684; found 273.11724.
H
16
N
4
S [M
93%) as a beige solid; m.p. 199–201 °C. R
EtOAc, 6:4). H NMR (400 MHz, CDCl
3
f
= 0.51 (petroleum ether/
): δ = 7.71 (d, J = 8.5 Hz,
H, 2 Har), 7.65 (s, 1 H, 5-H), 7.05 (t, J = 8.5 Hz, 2 H, 2 Har),
+
1
2
3
6
-(4-Fluorophenyl)-2-(morpholin-4-yl)imidazo[2,1-b][1,3,4]thia-
1
3
.52–3.36 [m, 4 H, 2 CH
2
(N)], 1.78–1.60 (m, 6 H, 3 CH
): δ = 164.9 (C ), 162.0 (d, J = 245.0 Hz,
), 141.7 (C ), 130.9 (d, J = 3.1 Hz, C ), 126.3 (d,
J = 7.9 Hz, 2 CHar), 115.6 (d, J = 21.7 Hz, 2 CHar), 108.8 (C-5),
9.7 [2 CH (N)], 25.0 (2 CH ), 24.1 (CH
) ppm. 19F NMR
376 MHz, CDCl ): δ = –115.71 ppm. IR (ATR diamond): ν˜ =
128, 2945, 2855, 1563, 1538, 1470, 1442, 1383, 1334, 1253, 1215,
2
) ppm.
C
diazole (6): The reaction was carried out as described in general
procedure A1 by using the corresponding bromo derivative
(
(
leum ether/EtOAc, 7:3). H NMR (400 MHz, CDCl
(
8
NMR (101 MHz, CDCl
-F), 142.7 (C
3
q
C
q
q
q
q
150 mg, 0.50 mmol, 1.0 equiv.) in morpholine (2 mL) to afford 6
139 mg, 91%) as a beige solid; m.p. 233–235 °C. R = 0.16 (petro-
): δ = 7.72
dd, J = 8.7, 5.4 Hz, 2 H, 2 Har), 7.68 (s, 1 H, 5-H), 7.06 (dd, J =
.7, 1.9 Hz, 2 H, 2 Har), 3.93–3.77 [m, 4 H, 2 CH (N)], 3.56–3.37
m, 4 H, 2 CH ): δ = 165.0
(O)] ppm. 13C NMR (101 MHz, CDCl
), 162.2 (d, J = 245.8 Hz, C -F), 143.1 (C ), 141.4 (C ), 130.7
d, J = 3.2 Hz, C ), 126.4 (d, J = 7.9 Hz, 2 CHar), 115.6 (d, J =
1.6 Hz, 2 CHar), 108.9 (CHar), 66.0 (2 CH ), 48.5 (2 CH ) ppm. thiadiazole (10): The reaction was carried out as described in gene-
): δ = –115.55 ppm. IR (ATR dia-
mond): ν˜ = 3129, 2972, 1537, 1471, 1409, 1234, 1152, 1033, 939,
f
4
(
3
1
2
2
2
1
3
3
2
–
1
153, 1126, 1013, 896, 836, 828, 737, 696 cm . HRMS (ESI): calcd.
[
2
3
for C15
H15FN
4
S [M + H]+ 303.10742; found 303.10759.
(C
q
q
q
q
(
q
6-(4-Fluorophenyl)-2-(4-methylpiperazin-1-yl)imidazo[2,1-b][1,3,4]-
2
2
2
19
F NMR (376 MHz, CDCl
3
ral procedure A1 by using the corresponding bromo derivative
(100 mg, 0.34 mmol, 1.0 equiv.) in N-methylpiperazine (2 mL) to
–1
8
38, 736, 704 cm . HRMS (ESI): calcd. for C14
H
13FN
4
OS [M +
afford 10 (95 mg, 89%) as a beige solid; m.p. 214–216 °C. R
(CH Cl /MeOH, 97:3). H NMR (400 MHz, CDCl
2 2 3
f
= 0.17
): δ = 7.71 (d,
J = 8.6 Hz, 2 H, 2 Har), 7.67 (s, 1 H, 5-H), 7.06 (t, J = 8.6 Hz, 2
H, 2 Har), 3.54–3.42 (m, 4 H, 2 CH ), 2.62–2.47 (m, 4 H, 2 CH ),
) ppm. C NMR (101 MHz, CDCl ): δ = 164.8
), 162.0 (d, J = 245.0 Hz, C -F), 142.9 (C ), 141.6 (C ), 130.8
d, J = 3.1 Hz, C ), 126.3 (d, J = 7.9 Hz, 2 CHar), 115.6 (d, J =
1.4 Hz, 2 CHar), 108.9 (C-5), 54.0 [2 CH (N)], 48.4 [2 CH (N)],
6.3 (CH ): δ = –115.89 ppm.
) ppm. 19F NMR (376 MHz, CDCl
+
1
H] 305.08669; found 305.08686.
-(Benzylamino)-6-(4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazole
7): The reaction was carried out as described in general procedure
A2 by using the corresponding bromo derivative (150 mg,
.50 mmol, 1.0 equiv.) in benzylamine (2 mL). The crude mixture
2
(
2
2
1
3
2
.35 (s, 3 H, CH
3
3
(
C
q
q
q
q
0
(
2
4
q
was purified by flash chromatography on silica gel (petroleum
ether/EtOAc, 4:6) to afford 7 (137 mg, 84 %) as a white solid;
2
2
1
3
3
m.p.194–196 °C. R
400 MHz, [D
H, 5-H), 7.77 (dd, J = 8.5, 5.6 Hz, 2 H, 2 Har), 7.42–7.32 (m, 4
H, 4 Har), 7.28 (m, 1 H, Har), 7.17 (dd, J = 8.8, 1.9 Hz, 2 H, 2
ar), 4.50 (d, J = 5.6 Hz, 2 H, CH
) ppm. 13C NMR (101 MHz,
), 161.0 (d, J = 243.0 Hz, C -F), 141.3
), 131.1 (d, J = 3.0 Hz, C ), 128.5 (2
f
= 0.15 (petroleum ether/EtOAc, 7:3). H NMR
IR (ATR diamond): ν˜ = 3138, 2946, 2853, 2801, 1562, 1536, 1474,
(
6
]DMSO): δ = 8.46 (t, J = 5.6 Hz, 1 H, NH), 8.22 (s,
–
1
1
287, 1251, 1218, 1145, 1047, 1003, 898, 834, 797, 737, 705 cm .
HRMS (ESI): calcd. for C15
S [M + H]+ 318.11832; found
18.11847.
1
H
16FN
5
3
H
2
[
(
D
6
]DMSO): δ = 161.6 (C
), 140.4 (C ), 137.9 (C
q
q
2-(Morpholin-4-yl)-6-(pyridin-4-yl)imidazo[2,1-b][1,3,4]thiadiazole
(11): The reaction was carried out as described in general procedure
C
q
q
q
q
CHar), 127.5 (2 CHar), 127.3 (CHar), 125.8 (d, J = 7.9 Hz, 2 CHar), A1 by using the corresponding bromo derivative (150 mg,
15.3 (d, J = 21.3 Hz, 2 CHar), 109.8 (CHar), 47.2 (CH 0.53 mmol, 1.0 equiv.) in morpholine (2 mL) to afford 11 (130 mg,
) ppm. 19F
NMR (376 MHz, [D ]DMSO): δ = –115.65 ppm. IR (ATR dia- 85%) as a pale brown solid; m.p. 248–250 °C. R = 0.53 (CH Cl
mond): ν˜ = 3254, 3033, 1531, 1485, 1408, 1352, 1223, 1153, 1093, MeOH, 9:1). H NMR (250 MHz, CDCl ): δ = 8.57 (d, J = 5.3 Hz,
S [M 2 H, 2 Har), 7.88 (s, 1 H, 5-H), 7.62 (d, J = 5.3 Hz, 2 H, 2 Har),
4.11–3.72 [m, 4 H, 2 CH (N)], 3.62–3.31 [m, 4 H, 2 CH (O)] ppm.
C NMR (63 MHz, CDCl ): δ = 165.4 (C ), 150.3 (2 CHar), 142.3
), 141.7 (C ), 141.0 (C ), 119.0 (2 CHar), 111.2 (C-5), 66.0 [2
CH (N)], 48.4 [2 CH (O)] ppm. IR (ATR diamond): ν˜ = 1602,
552, 1467, 1272, 1237, 1112, 1036, 902, 827, 752, 699 cm . HRMS
ESI): calcd. for C13
OS [M + H]+ 288.09136; found
1
2
6
f
2
2
/
1
3
–
1
1
+
025, 840, 813, 720 cm . HRMS (ESI): calcd. for C17H13FN
4
+
H] 325.09177; found 325.09184.
-(Butylamine)-6-(4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazole
8): The reaction was carried out as described in general procedure
A2 by using the corresponding bromo derivative (150 mg,
.50 mmol, 1.0 equiv.) in n-butylamine (2 mL). The crude mixture
2
2
1
3
3
q
2
(
(
C
q
q
q
2
2
–
1
1
0
(
2
13 5
H N
was purified by flash chromatography on silica gel (petroleum
88.09166.
ether/EtOAc, 4:6) to afford 8 (115 mg, 79%) as a beige solid; m.p.
1
1
62–164 °C. R
250 MHz, CDCl
H, 5-H), 7.06 (t, J = 8.8 Hz, 2 H, 2 Har), 4.98 (t, J = 5.7 Hz, 1 H, by using the corresponding bromo derivative (500 mg, 1.69 mmol,
NH), 3.37 (td, J = 7.1, 5.7 Hz, 2 H, NHCH CH CH CH ), 1.82– 1.0 equiv.) in morpholine (8 mL) to afford 12 (470 mg, 92%) as a
.56 (m, 2 H, NHCH CH CH CH ), 1.54–1.27 (m, 2 H, beige solid; m.p. 238–240 °C. R = 0.45 (petroleum ether/EtOAc,
C H ) , 0 . 9 6 ( t , J = 7 . 3 H z , 3 H , 5:5). H NMR (400 MHz, [D ]DMSO): δ = 9.36 (s, 1 H, OH), 8.25
) ppm. 13C NMR (63 MHz, CDCl
): δ = (s, 1 H, 5-H), 7.25–7.18 (m, 2 H, Har), 7.14 (t, J = 7.8 Hz, 1 H,
-F), 142.9 (C ), 141.1 (C ), ar), 6.63 (dd, J = 7.8, 1.1 Hz, 1 H, Har), 3.79–3.68 [m, 4 H, 2
), 126.3 (d, J = 8.0 Hz, 2 CHar), 115.5 (d, CH (N)], 3.49–3.38 [m, 4 H, 2 CH
(O)] ppm. 13C NMR (101 MHz,
CH CH CH ), [D ]DMSO): δ = 164.8 (C ), 157.6 (C ), 142.6 (C ), 140.3 (C ),
CH CH ), 13.8 135.6 (CHar), 129.5 (C ), 115.2 (CHar), 113.7 (CHar), 111.1 (CHar),
) ppm. 19F NMR (376 MHz, CDCl
): δ = 110.0 (CHar), 65.1 [2 CH (N)], 47.9 [2 CH (O)] ppm. IR (ATR dia-
115.43 ppm. IR (ATR diamond): ν˜ = 3217, 3025, 2929, 2863,
f
= 0.72 (petroleum ether/EtOAc, 1:9). H NMR
2-(Morpholin-4-yl)-6-(3-phenol)imidazo[2,1-b][1,3,4]thiadiazole (12):
(
3
): δ = 7.71 (t, J = 8.8 Hz, 2 H, 2 Har), 7.68 (s, 1 The reaction was carried out as described in general procedure A1
2
2
2
3
1
2
2
2
3
f
1
N H C H
2
C H
2
C H
CH
2
3
6
NHCH CH
2
2
CH
2
3
3
162.5 (C
q
), 162.1 (d, J = 247.3 Hz, C
q
q
q
H
130.7 (d, J = 3.2 Hz, C
q
2
2
J = 22.6 Hz, 2 CHar), 109.1 (C-5), 45.1 (NHCH
1.4 (NHCH CH CH CH ), 20.1 (NHCH CH
NHCH CH CH CH
2
2
2
3
6
q
q
q
q
3
(
2
2
2
3
2
2
2
3
q
2
2
2
3
3
2
2
–
1
mond): ν˜ = 3350, 3152, 1596, 1552, 1453, 1440, 1379, 1271, 1224,
–
1
–1
570, 1544, 1490, 1458, 1233, 1154, 836, 733 cm . HRMS (ESI):
1103, 1022, 901, 872, 796, 738, 689 cm . HRMS (ESI): calcd. for
+
14 14 4 2
C H N O
S [M + H]+ 303.09102; found 303.09104.
calcd. for C14
H
15FN
4
S [M + H] 291.10742; found 291.10757.
6
-(4-Fluorophenyl)-2-(piperidin-1-yl)imidazo[2,1-b][1,3,4]thiadi-
6-Phenyl-2-(2-oxo-1-piperidinyl)imidazo[2,1-b][1,3,4]thiadiazole
(14): The reaction was carried out as described in general procedure
B by using the corresponding bromo derivative (100 mg,
azole (9): The reaction was carried out as described in general pro-
cedure A1 by using the corresponding bromo derivative (100 mg,
0
.34 mmol, 1.0 equiv.) in piperidine (2 mL) to afford 9 (96 mg, 0.36 mmol, 1.0 equiv.) and δ-valerolactam (53 mg, 0.54 mmol,
6938
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6932–6942

N
S Ar versus Buchwald–Hartwig Amination/Amidation
1
.5 equiv.). The crude product was purified by flash chromatog-
raphy on silica gel (petroleum ether/EtOAc, 7:3 to 5:5) to afford 14
104 mg, 97%) as a beige solid; m.p. 231–233 °C. R = 0.19 (petro-
): δ = 7.85 (s,
H, 5-H), 7.81 (d, J = 7.8 Hz, 2 H, 2 Har), 7.39 (t, J = 7.8 Hz, 2 1113, 1024, 753, 717, 661 cm . HRMS (ESI): calcd. for
H, 2 Har), 7.30–7.22 (m, 1 H, Har), 4.25–3.84 [m, 2 H, CH (N)],
S [M + H]+ 329.10667; found 329.10686.
.74–2.55 [m, 2 H, CH (C=O)], 2.08–1.85 (m, 4 H, 2 CH ) ppm.
C NMR (101 MHz, CDCl ): δ = 170.0 (C=O), 155.5 (C ), 145.3
), 145.2 (C ), 134.4 (C ), 128.8 (2 CHar), 127.3 (CHar), 125.1 (2
CHar), 108.4 (C-5), 48.4 [CH (N)], 32.8 [CH (C=O)], 22.4 (CH ),
) ppm. IR (ATR diamond): ν˜ = 1655, 1518, 1470, 1399,
(C
123.0 (C
48.4 [CH
(ATR diamond): ν˜ = 1658, 1519, 1469, 1400, 1283, 1241, 1172,
q
), 155.2 (C
), 121.0 (CHar), 112.8 (CHar), 110.9 (C-5), 55.5 (OCH
(N)], 32.9 [CH (C=O)], 22.4 (CH ), 19.9 (CH ) ppm. IR
q
), 144.1 (C
q
), 140.6 (C
q
), 127.8 (CHar), 127.6 (CHar),
q
3
),
(
f
2
2
2
2
1
leum ether/EtOAc, 7:3). H NMR (400 MHz, CDCl
1
3
–
1
2
16 16 4 2
C H N O
2
2
2
13
6-(4-Methylphenyl)-2-(2-oxo-1-piperidinyl)imidazo[2,1-b][1,3,4]-
thiadiazole (18): The reaction was carried out as described in gene-
ral procedure B by using the corresponding bromo derivative
3
q
(C
q
q
q
2
2
2
(
100 mg, 0.34 mmol, 1.0 equiv.) and δ-valerolactam (51 mg,
1
1
9.9 (CH
299, 1272, 1169, 959, 735, 692, 667 cm . HRMS (ESI): calcd. for
2
–1
0.51 mmol, 1.5 equiv.). The crude product was purified by flash
chromatography on silica gel (petroleum ether/EtOAc, 7:3 to 5:5)
+
C
15
H
14
N
4
OS [M + H] 299.09611; found 299.09645.
f
to afford 18 (103 mg, 97%) as a yellow solid; m.p. Ͼ260 °C. R =
1
6
-(4-Methoxyphenyl)-2-(2-oxo-1-piperidinyl)imidazo[2,1-b][1,3,4]-
0.13 (petroleum ether/EtOAc, 7:3). H NMR (250 MHz, CDCl
δ = 7.81 (s, 1 H, 5-H), 7.71 (d, J = 8.1 Hz, 2 H, 2 Har), 7.20 (d, J
= 8.1 Hz, 2 H, 2 Har), 4.05 [t, J = 6.0 Hz, 2 H, CH (N)], 2.67 [t, J
(C=O)], 2.37 (s, 3 H, CH ), 2.14–1.82 (m, 4 H,
) ppm. C NMR (101 MHz, CDCl ): δ = 170.0 (C=O), 155.4
), 145.5 (C ), 145.0 (C ), 137.1 (C ), 131.6 (C ), 129.5 (2 CHar),
125.0 (2 CHar), 108.0 (C-5), 48.4 [CH (N)], 32.9 [CH (C=O)], 22.4
(CH ), 21.4 (CH ), 19.9 (CH ) ppm. IR (ATR diamond): ν˜ = 3131,
δ = 7.78 (s, 1 H, 5-H), 7.74 (d, J = 8.9 Hz, 2 H, 2 Har), 6.94 (d, J 1656, 1518, 1457, 1394, 1298, 1270, 1255, 1177, 960, 828, 750,
3
):
thiadiazole (15): The reaction was carried out as described in gene-
ral procedure B by using the corresponding bromo derivative
2
(
100 mg, 0.32 mmol, 1.0 equiv.) and δ-valerolactam (48 mg, = 6.6 Hz, 2 H, CH
2
3
1
3
0.48 mmol, 1.5 equiv.). The crude product was purified by flash
2 CH
(C
2
3
chromatography on silica gel (petroleum ether/EtOAc, 7:3 to 5:5)
to afford 15 (23 mg, 22%) as a yellow solid; m.p. 222–224 °C. R
q
q
q
q
q
f
=
2
2
1
0
.13 (petroleum ether/EtOAc, 6:4). H NMR (400 MHz, CDCl
3
):
2
3
2
–
1
+
=
8.9 Hz, 2 H, 2 Har), 4.07 [t, J = 6.1 Hz, 2 H, CH
H, OCH ), 2.70 [t, J = 6.6 Hz, 2 H, CH (C=O)], 2.17–1.79 (m, 4
H) ppm. 13C NMR (101 MHz, CDCl
): δ = 170.0 (C=O), 159.2
), 127.2 (C ), 126.4 (2 CHar),
14.3 (2 CHar), 107.4 (C-5), 55.5 (OCH ), 48.4 [CH (N)], 32.9
(C=O)], 22.5 (CH ), 20.0 (CH ) ppm. IR (ATR diamond): ν˜
2
(N)], 3.84 (s, 3 692 cm . HRMS (ESI): calcd. for C16
16 4
H N OS [M + H]
3
2
313.11176; found 313.11229.
3
6
-(4-Fluorophenyl)-2-(2-oxo-1-piperidinyl)imidazo[2,1-b][1,3,4]-
(C
q
), 155.4 (C
q
), 145.3 (C
q
), 145.0 (C
q
q
thiadiazole (19): The reaction was carried out as described in gene-
ral procedure B by using the corresponding bromo derivative
1
3
2
[CH
2
2
2
(
100 mg, 0.34 mmol, 1.0 equiv.) and δ-valerolactam (50 mg,
=
1660, 1518, 1466, 1399, 1297, 1244, 1170, 1107, 1027, 840, 752,
92 cm–1. HRMS (ESI): calcd. for C16
S [M + H]+
0.50 mmol, 1.5 equiv.). The crude product was purified by flash
chromatography on silica gel (petroleum ether/EtOAc, 7:3 to 5:5)
6
3
H
16
N
4
O
2
29.10667; found 329.10678.
f
to afford 19 (103 mg, 97%) as a beige solid; m.p. 258–260 °C. R =
1
6
-(3-Methoxyphenyl)-2-(2-oxo-1-piperidinyl)imidazo[2,1-b][1,3,4]-
0.16 (petroleum ether/EtOAc, 3:7). H NMR (400 MHz, CDCl
δ = 7.79 (s, 1 H, 5-H), 7.78–7.73 (m, 2 H, 2 Har), 7.11–7.04 (m, 2
H, 2 Har), 4.05 [t, J = 6.1 Hz, 2 H, CH (N)], 2.68 [t, J = 6.6 Hz, 2
3
):
thiadiazole (16): The reaction was carried out as described in gene-
ral procedure B by using the corresponding bromo derivative
2
1
3
(
100 mg, 0.32 mmol, 1.0 equiv.) and δ-valerolactam (48 mg, H, CH
2
(C=O)], 2.14–1.82 (m, 4 H, 2 CH
2
) ppm. C NMR
): δ = 170.1 (C=O), 162.3 (d, J = 246.3 Hz, C
), 145.2 (C ), 130.6 (d, J = 3.2 Hz, C
126.7 (d, J = 8.0 Hz, 2 CHar), 115.7 (d, J = 22.1 Hz, 2 CHar), 108.1
0
.48 mmol, 1.5 equiv.). The crude product was purified by flash
chromatography on silica gel (petroleum ether/EtOAc, 7:3 to 5:5)
to afford 16 (102 mg, 86%) as a beige solid; m.p. 207–209 °C. R
(101 MHz, CDCl
3
q
-
F), 155.5 (C
q
), 144.5 (C
q
q
q
),
f
=
1
19
0
.11 (petroleum ether/EtOAc, 7:3). H NMR (250 MHz, CDCl
3
):
(C-5), 48.4 (CH
NMR (376 MHz, CDCl
ν˜ = 2945, 1660, 1519, 1471, 1399, 1296, 1209, 1171, 956, 846, 733,
2
), 32.8 (CH
2
), 22.4 (CH
2
), 19.9 (CH
2
) ppm.
F
δ = 7.84 (s, 1 H, 5-H), 7.45–7.40 (m, 1 H, Har), 7.40–7.24 (m, 2 H,
3
): δ = –115.19 ppm. IR (ATR diamond):
2 ar), 6.87–6.78 (m, 1 H, Har), 4.04 [t, J = 6.2 Hz, 2 H, CH
3.88 (s, 3 H, OCH ), 2.67 [t, J = 6.6 Hz, 2 H, CH (C=O)], 2.09–
.83 (m, 4 H) ppm. 13C NMR (63 MHz, CDCl
1 ): δ = 170.0 (C=O),
160.1 (C ), 155.5 (C ), 145.2 (C ), 145.1 (C ), 135.8 (C ), 129.8
H
2
(N)],
–
1
+
3
2
693 cm . HRMS (ESI): calcd. for C15
317.08669; found 317.08704.
4
H13FN OS [M + H]
3
q
q
q
q
q
2
-(2-Oxo-1-piperidinyl)-6-(4-trifluoromethylphenyl)imidazo[2,1-b]-
(CHar), 117.5 (CHar), 113.6 (CHar), 109.9 (CHar), 108.6 (C-5), 55.5
(OCH ), 48.4 [CH (N)], 32.8 [CH (C=O)], 22.4 (CH ), 19.9
(CH ) ppm. IR (ATR diamond): ν˜ = 1657, 1610, 1578, 1519, 1473,
[1,3,4]thiadiazole (20): The reaction was carried out as described in
3
2
2
2
general procedure B by using the corresponding bromo derivative
(100 mg, 0.29 mmol, 1.0 equiv.) and δ-valerolactam (43 mg,
0.43 mmol, 1.5 equiv.). The crude product was purified by flash
chromatography on silica gel (ethyl acetate/petroleum ether, 3:7 to
2
–1
1399, 1272, 1216, 1166, 1046, 958, 734 cm . HRMS (ESI): calcd.
+
16 4 2
for C16H N O S [M + H] 329.10667; found 329.10694.
6
-(2-Methoxyphenyl)-2-(2-oxo-1-piperidinyl)imidazo[2,1-b][1,3,4]-
5:5) to afford 20 (104 mg, 98 %) as a pale yellow solid; m.p.
1
thiadiazole (17): The reaction was carried out as described in gene-
Ͼ260 °C. R
f
= 0.20 (petroleum ether/EtOAc, 7:3). H NMR
ral procedure B by using the corresponding bromo derivative
(250 MHz, CDCl
3
): δ = 7.94 (s, 1 H, 5-H), 7.92 (d, J = 8.4 Hz, 2
(
100 mg, 0.32 mmol, 1.0 equiv.) and δ-valerolactam (48 mg, H, 2 Har), 7.64 (d, J = 8.4 Hz, 2 H, 2 Har), 4.09 [t, J = 6.0 Hz, 2
0
.48 mmol, 1.5 equiv.). The crude product was purified by flash
H, CH
H, 2 CH
155.8 (C
(C ), 125.6 (m, 2 CHar), 125.0 (2 CHar), 109.3 (C-5), 48.4 [CH
2
2
(N)], 2.72 [t, J = 6.6 Hz, 2 H, CH
2
(C=O)], 2.17–1.89 (m, 4
) ppm. C NMR (101 MHz, CDCl ): δ = 170.0 (C=O),
), 145.6 (C ), 143.7 (C ), 137.6 (C ), 129.1 (C ), 128.7
(N)],
) ppm. F NMR
): δ = –62.40 ppm. IR (ATR diamond): ν˜ = 3144,
2
(N)], 3.96 (s, 3 H, 1666, 1523, 1474, 1269, 1201, 1160, 1112, 1102, 1072, 847,
1
3
chromatography on silica gel (petroleum ether/EtOAc, 6:4 to 4:6)
to afford 17 (115 mg, 97%) as a pale yellow solid; m.p. 239–241 °C.
R
2
3
q
q
q
q
q
1
f
= 0.30 (petroleum ether/EtOAc, 5:5). H NMR (250 MHz,
q
1
9
CDCl
.19 (m, 1 H, Har), 7.06 (dd, J = 9.0, 6.0 Hz, 1 H, Har), 6.96 (d, J (376 MHz, CDCl
8.2 Hz, 1 H, Har), 4.10–4.00 [m, 2 H, CH
OCH ), 2.73–2.59 [m, 2 H, CH (C=O)], 2.09–1.87 (m, 4 H, 2 706 cm . HRMS (ESI): calcd. for C16
CH
) ppm. 13C NMR (63 MHz, CDCl
3 2 2 2
): δ = 8.26 (d, J = 7.8 Hz, 1 H, Har), 8.19 (s, 1 H, 5-H), 7.30– 32.7 [CH (C=O)], 22.3 (CH ), 19.8 (CH
7
=
3
–
1
+
3
2
13 3 4
H F N OS [M + H]
2
3
): δ = 170.0 (C=O), 156.0 367.08349; found 367.08392.
Eur. J. Org. Chem. 2015, 6932–6942
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6939

C. Copin, S. Massip, J.-M. Léger, C. Jarry, F. Buron, S. Routier
FULL PAPER
6
-(3-Nitrophenyl)-2-(2-oxo-1-piperidinyl)imidazo[2,1-b][1,3,4]- 1 H, 5-H), 4.04 [t, J = 6.2 Hz, 2 H, CH
2
(N)], 2.68 [t, J = 6.6 Hz,
), 2.06–1.88 (m, 4 H, 2
): δ = 169.9 (C=O), 154.8
), 109.5 (C-5), 48.3 [CH (N)], 32.8
), 20.0 (CH ), 15.0 (CH ) ppm. IR (ATR
diamond): ν˜ = 2952, 1655, 1525, 1462, 1399, 1286, 1170, 958,
thiadiazole (21): The reaction was carried out as described in gene-
ral procedure B by using the corresponding bromo derivative
2 H, CH
CH ) ppm. C NMR (101 MHz, CDCl
), 143.8 (C ), 142.2 (C
[CH (C=O)], 22.5 (CH
2 3
(C=O)], 2.35 (s, 3 H, CH
1
3
2
3
(
100 mg, 0.31 mmol, 1.0 equiv.) and δ-valerolactam (46 mg, (C
q
q
q
2
0
.46 mmol, 1.5 equiv.). The crude product was purified by flash
2
2
2
3
chromatography on silica gel (petroleum ether/EtOAc, 3:7 to 5:5)
to afford 21 (85 mg, 80%) as a yellow solid; m.p. Ͼ260 °C. R
0
–
1
+
f
=
3
):
660 cm . HRMS (ESI): calcd. for C10
237.08046; found 237.08087.
12 4
H N OS [M + H]
1
.25 (petroleum ether/EtOAc, 6:4). H NMR (400 MHz, CDCl
δ = 8.62 (s, 1 H, Har), 8.18 (d, J = 8.1 Hz, 1 H, Har), 8.10 (d, J =
6
-(Phenyl)-2-(2-oxo-1-pyrrolidinyl)imidazo[2,1-b][1,3,4]thiadiaz-
8
4
1
.1 Hz, 1 H, Har), 7.99 (s, 1 H, 5-H), 7.56 (t, J = 8.1 Hz, 1 H, Har),
.19–4.05 [m, 2 H, CH (N)], 2.79–2.67 [m, 2 H, CH (C=O)], 2.14–
) ppm. 1 C NMR (63 MHz, CDCl
.91 (m, 4 H, 2 CH ): δ = 170.2
), 148.9 (C ), 145.9 (C ), 143.1 (C ), 136.2 (C ),
30.8 (CHar), 129.8 (CHar), 121.9 (CHar), 119.8 (CHar), 109.5 (C-
), 48.6 [CH (N)], 32.9 [CH (C=O)], 22.5 (CH ), 20.0 (CH ) ppm.
ole (26): The reaction was carried out as described in general pro-
cedure B by using the corresponding bromo derivative (100 mg,
2
2
3
2
3
0
1
.32 mmol, 1.0 equiv.) and 2-pyrrolidinone (36 µL, 0.48 mmol,
.5 equiv.). The crude product was diluted with water (5 mL), and
(C=O), 156.2 (C
q
q
q
q
q
1
5
the mixture was extracted with dichloromethane (2ϫ 15 mL). The
combined organic layers were dried with MgSO and filtered. The
solvent was removed under reduced pressure, and a minimum of
dichloromethane and a large excess amount of petroleum ether
were added to the resulting material. After cooling at 0 °C, the
2
2
2
2
4
IR (ATR diamond): ν˜ = 3150, 1667, 1522, 1475, 1401, 1343, 1295,
–
1
1
[
165, 956, 738, 684 cm . HRMS (ESI): calcd. for C15
13 5 3
H N O S
M + H]+ 344.08119; found 344.08141.
6
-(3-Hydroxyphenyl)-2-(2-oxo-1-piperidinyl)imidazo[2,1-b][1,3,4]- precipitate was removed by filtration to afford 26 (64 mg, 63%) as
thiadiazole (22): The reaction was carried out as described in gene-
ral procedure B by using the corresponding bromo derivative
a pale brown solid; m.p. Ͼ260 °C. R
f
= 0.11 (petroleum ether/
1
EtOAc, 4:6). H NMR (400 MHz, [D ]DMSO): δ = 8.53 (s, 1 H,
6
(
0
100 mg, 0.34 mmol, 1.0 equiv.) and δ-valerolactam (50 mg, 5-H), 7.84 (d, J = 7.4 Hz, 2 H, 2 Har), 7.39 (t, J = 7.4 Hz, 2 H, 2
.51 mmol, 1.5 equiv.). The crude product was purified by flash ar), 7.25 (t, J = 7.4 Hz, 1 H, Har), 4.02 [t, J = 7.0 Hz, 2 H,
chromatography on silica gel (CH Cl /MeOH, 100:0 to 97:3) to CH (N)], 2.67 [t, J = 7.8 Hz, 2 H, CH (C=O)], 2.31–2.11 (m, 2 H,
afford 22 (46 mg, 43%) as a beige solid; m.p. Ͼ260 °C. R = 0.19 CH ) ppm. C 135 DEPT NMR (101 MHz, [D ]DMSO): δ =
]DMSO): δ 128.4 (2 CHar), 126.7 (CHar), 124.2 (2 CHar), 47.4 [CH (N)], 30.7
9.40 (s, 1 H, OH), 8.43 (s, 1 H, 5-H), 7.33–7.22 (m, 2 H, 2 Har), [CH (C=O)], 17.5 (CH ) ppm. IR (ATR diamond): ν˜ = 3133, 1686,
.16 (t, J = 7.8 Hz, 1 H, Har), 6.78–6.50 (m, 1 H, Har), 3.99 [t, J = 1530, 1477, 1442, 1392, 1299, 1272, 1071, 936, 742, 696 cm
.1 Hz, 2 H, CH (N)], 2.63 [d, J = 6.4 Hz, 2 H, CH (C=O)], 2.02– HRMS (ESI): calcd. for C14
OS [M + H]+ 285.08046; found
.72 (m, 4 H, 2 CH ]DMSO): δ = 285.08066.
) ppm. 13C NMR (101 MHz, [D
70.5 (C=O), 157.6 (C ), 154.9 (C ), 144.2 (C ), 143.6 (C ), 135.5
H
2
2
2
2
1
3
f
2
6
1
(
=
petroleum ether/EtOAc, 4:6). H NMR (400 MHz, [D
6
2
2
2
–
1
7
6
1
1
(
(
(
.
2
2
12 4
H N
2
6
q
q
q
q
6
-Phenyl-2-(N-phenylamine)imidazo[2,1-b][1,3,4]thiadiazole (27):
C
q
), 129.5 (CHar), 115.5 (CHar), 114.0 (CHar), 111.4 (CHar), 109.3
The reaction was carried out as described in general procedure B
by using the corresponding bromo derivative (100 mg, 0.32 mmol,
1.0 equiv.) and aniline (49 μL, 0.48 mmol, 1.5 equiv.). The crude
product was purified by flash chromatography on silica gel (petro-
leum ether/EtOAc, 3:7 to 5:5) to afford 27 (101 mg, 96%) as a pale
2 2 2
C-5), 48.1 [CH (N)], 32.2 [CH (C=O)], 21.5 (CH ), 19.0
2
CH ) ppm. IR (ATR diamond): ν˜ = 3151, 2958, 1661, 1459, 1437,
–1
1
C
398, 1289, 1220, 1165, 733, 688 cm . HRMS (ESI): calcd. for
+
15 14 4 2
H N O S [M + H] 315.09102; found 315.09132.
6
-(Ethylcarboxylate)-2-(2-oxo-1-piperidinyl)imidazo[2,1-b][1,3,4]- brown solid; m.p. Ͼ260 °C. R
f
= 0.13 (petroleum ether/EtOAc, 7:3).
]DMSO): δ = 10.51 (s, 1 H, NH), 8.43 (s,
1 H, 5-H), 7.81 (d, J = 7.5 Hz, 2 H, 2 Har), 7.58 (d, J = 7.9 Hz, 2
1
thiadiazole (24): The reaction was carried out as described in gene-
ral procedure B by using the corresponding bromo derivative
H NMR (400 MHz, [D
6
(
0
100 mg, 0.36 mmol, 1.0 equiv.) and δ-valerolactam (54 mg, H, 2 Har), 7.46–7.32 (m, 4 H, 4 Har), 7.23 (t, J = 7.2 Hz, 1 H, Har),
.54 mmol, 1.5 equiv.). The crude product was purified by flash ]-
7.07 (t, J = 7.2 Hz, 1 H, Har) ppm. 13C NMR (101 MHz, [D
chromatography on silica gel (petroleum ether/EtOAc ether, 5:5 to DMSO): δ = 157.5 (C ), 142.8 (C ), 140.0 (C ), 139.6 (C ), 134.3
:8) to afford 24 (48 mg, 45%) as a beige solid; m.p. 131–135 °C. (C ), 129.2 (2 CHar), 128.6 (2 CHar), 126.6 (CHar), 124.1 (2 CHar),
6
q
q
q
q
2
R
q
1
f
= 0.14 (petroleum ether/EtOAc, 5:5). H NMR (250 MHz,
122.6 (CHar), 117.8 (2 CHar), 110.3 (C-5) ppm. IR (ATR diamond):
CDCl ): δ = 8.20 (s, 1 H, 5-H), 4.40 (q, J = 7.1 Hz, 2 H, CH CH
3
2
3
), ν˜ = 2780, 1630, 1565, 1539, 1496, 1470, 1438, 1314, 1252, 742, 711,
–
1
+
4.14–4.02 [m, 2 H, CH
2
(N)], 2.77–2.66 [m, 2 H, CH
2
(C=O)], 2.15– 686 cm . HRMS (ESI): calcd. for C16
H
12
N
4
S [M + H] 293.08554;
1
3
1
.88 (m, 4 H, 2 CH ), 1.42 (q, J = 7.1 Hz, 3 H, CH
2
2
CH
3
) ppm.
C
found 293.08587.
NMR (101 MHz, CDCl
), 145.9 (C ), 136.5 (C
CH (N)], 32.9 [CH (C=O)], 22.4 (CH
and CH ) ppm. IR (ATR diamond): ν˜ = 3137, 2942, 1713, 1664,
3
): δ = 170.4 (C=O), 162.8 (COOEt), 157.6
), 117.6 (C-5), 61.0 (CH CH ), 48.6
), 19.9 (CH ), 14.5 (CH
2
2
-(4-Methoxyphenylamine)-6-phenylimidazo[2,1-b][1,3,4]thiadi-
(
[
C
q
q
q
2
3
azole (28): The reaction was carried out as described in general
procedure B by using the corresponding bromo derivative (100 mg,
0.36 mmol, 1.0 equiv.) and 4-methoxyaniline (67 mg, 0.54 mmol,
1.5 equiv.). The crude product was purified by flash chromatog-
raphy on silica gel (petroleum ether/EtOAc, 7:3 to 4:6) to afford 28
2
2
2
2
3
–
1
1
520, 1473, 1270, 1338, 1299, 1189, 1133, 966, 767, 683 cm .
+
14 4 3
HRMS (ESI): calcd. for C12H N O S [M + H] 295.08594; found
295.08609.
(
99 mg, 85%) as a pale brown solid; m.p. 242–244 °C. R
f
= 0.14
]DMSO): δ
= 10.32 (s, 1 H, NH), 8.39 (s, 1 H, 5-H), 7.81 (t, J = 7.5 Hz, 2 H,
2 Har), 7.50 (d, J = 9.0 Hz, 2 H, 2 Har), 7.38 (t, J = 7.5 Hz, 2 H, 2
1
6
-Methyl-2-(2-oxo-1-piperidinyl)imidazo[2,1-b][1,3,4]thiadiazole (petroleum ether/EtOAc, 3:7). H NMR (400 MHz, [D
6
(25): The reaction was carried out as described in general procedure
B by using the corresponding bromo derivative (100 mg,
0
1
.46 mmol, 1.0 equiv.) and δ-valerolactam (68 mg, 0.69 mmol,
.5 equiv.). The crude product was purified by flash chromatog-
H
H
ar), 7.23 (t, J = 7.5 Hz, 1 H, Har), 6.99 (d, J = 9.0 Hz, 2 H, 2
1
3
ar), 3.76 (s, 3 H, OCH
), 155.1 (C
), 128.5 (2 CHar), 126.5 (CHar), 124.1 (2 CHar), 119.8 (2 CHar),
114.4 (2 CHar), 110.2 (C-5), 55.3 (OCH ) ppm. IR (ATR diamond):
3
) ppm. C NMR (101 MHz, [D
6
]DMSO):
raphy on silica gel (petroleum ether/EtOAc, 4:6) to afford 25
94 mg, 87%) as a beige solid; m.p. 187–189 °C. R = 0.19 (petro-
): δ = 7.33 (s,
δ = 158.0 (C
(C
q
q
), 142.6 (C ), 140.0 (C ), 134.4 (C
q
q
q
), 132.9
(
f
q
1
leum ether/EtOAc, 5:5). H NMR (400 MHz, CDCl
3
3
6940
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6932–6942

N
S Ar versus Buchwald–Hartwig Amination/Amidation
ν˜ = 2845, 1604, 1510, 1458, 1435, 1242, 1225, 1180, 1027, 768, 718,
flash chromatography on silica gel (CH
2 2
Cl /MeOH, 1:0 to 9:1) to
6
3
89 cm–1. HRMS (ESI): calcd. for C17
23.09611; found 323.09640.
H
14
N
4
OS [M + H]+
afford 33 (68 mg, 58%) as a brown solid; m.p. 242–244 °C. R =
f
1
2 2 6
0.18 (CH Cl /MeOH, 9:1). H NMR (250 MHz, [D ]DMSO): δ =
1
8
=
0.46 (s, 1 H, NH), 8.42–8.33 (m, 2 H, 5-H + Har), 7.92 (dd, J =
.9, 2.9 Hz, 1 H, Har), 7.80 (d, J = 7.7 Hz, 2 H, 2 Har), 7.38 (t, J
2
-[(2-Methoxyphenyl)amine]-6-phenylimidazo[2,1-b][1,3,4]thiadi-
azole (29): The reaction was carried out as described in general
procedure B by using the corresponding bromo derivative (100 mg,
7.7 Hz, 2 H, 2 Har), 7.22 (t, J = 7.7 Hz, 1 H, Har), 6.89 (d, J =
1
3
8
.9 Hz, 1 H, Har), 3.85 (s, 3 H, OCH
]DMSO): δ = 159.4 (C ), 158.1 (C
36.7 (CHar), 134.3 (C ), 130.9 (C ), 130.6 (CHar), 128.5 (2 CHar),
26.6 (CHar), 124.1 (2 CHar), 110.6 (CHar), 110.3 (C-5), 53.2
) ppm. IR (ATR diamond): ν˜ = 2672, 1568, 1489, 1469,
3
) ppm. C NMR (101 MHz,
0
1
.36 mmol, 1.0 equiv.) and 2-methoxyaniline (87 mg, 0.54 mmol,
.5 equiv.). The crude product was purified by flash chromatog-
[D
6
q
q
), 142.7 (C ), 140.1 (C ),
q
q
1
1
q
q
raphy on silica gel (petroleum ether/EtOAc, 6:4 to 4:6) to afford 29
(
(
105 mg, 91%) as a pale yellow solid; m.p. 193–195 °C. R
petroleum ether/EtOAc, 7:3). H NMR (250 MHz, [D
f
= 0.22
]DMSO): δ
9.96 (s, 1 H, NH), 8.39 (s, 1 H, 5-H), 8.15–8.07 (m, 1 H, Har),
(
OCH
3
1
6
–
1
1439, 1383, 1276, 1241, 1025, 771, 718, 691 cm . HRMS (ESI):
=
7
OS [M + H]+ 324.09136; found 324.09169.
13 5
calcd. for C16H N
.87–7.73 (m, 2 H, 2 Har), 7.41–7.33 (m, 2 H, 2 Har), 7.23 (dt, J =
9
.4, 4.4 Hz, 1 H, Har), 7.11–6.96 (m, 3 H, 3 Har), 3.89 (s, 3 H,
6
(
-(4-Fluorophenyl)-2-(phenylamine)imidazo[2,1-b][1,3,4]thiadiazole
34): The reaction was carried out as described in general procedure
B by using the corresponding bromo derivative (100 mg,
.34 mmol, 1.0 equiv.) and aniline (46 μL, 0.50 mmol, 1.5 equiv.).
OCH
3
) ppm. 13C NMR (101 MHz, [D
6
]DMSO): δ = 158.3 (C
), 134.4 (C ), 128.5 (2 CHar + C
q
),
),
1
1
48.7 (C
q
), 142.7 (C
q
), 140.9 (C
q
q
q
26.5 (CHar), 124.1 (2 CHar), 123.6 (CHar), 120.6 (CHar), 119.4
) ppm. IR (ATR dia-
0
(CHar), 111.3 (CHar), 110.0 (C-5), 55.8 (OCH
3
The crude product was purified by flash chromatography on silica
gel (petroleum ether/EtOAc, 7:3 to 5:5) to afford 34 (101 mg, 97%)
as a pale brown solid; m.p. 257–259 °C. R
EtOAc, 7:3). H NMR (400 MHz, [D
mond): ν˜ = 3142, 1563, 1523, 1463, 1433, 1248, 1110, 1026, 750,
18, 692 cm–1. HRMS (ESI): calcd. for C17
23.09611; found 323.09635.
14 4
H N
OS [M + H]+
7
3
f
= 0.17 (petroleum ether/
1
6
]DMSO): δ = 10.51 (s, 1 H,
6
-Phenyl-2-[4-(trifluoromethyl)phenylamine]imidazo[2,1-b][1,3,4]-
NH), 8.41 (s, 1 H, 5-H), 7.93–7.73 (m, 2 H, 2 Har), 7.67–7.49 (m,
2 H, 2 Har), 7.39 (dd, J = 8.7, 7.4 Hz, 2 H, 2 Har), 7.21 (t, J =
8.8 Hz, 2 H, 2 Har), 7.13–6.97 (m, 1 H, Har) ppm. 13C NMR
thiadiazole (30): The reaction was carried out as described in gene-
ral procedure B by using the corresponding bromo derivative
(
(
100 mg, 0.36 mmol, 1.0 equiv.) and 4-(trifluoromethyl)aniline
69 μL, 0.54 mmol, 1.5 equiv.). The crude product was purified by
(101 MHz, [D
(C ), 157.5 (C
3.0 Hz, C ), 129.2 (2 CHar), 126.0 (d, J = 8.1 Hz, 2 CHar), 122.6
6
]DMSO): δ = 161.1 (d, J = 243.3 Hz, C
q
-F), 159.9
q
q
), 141.9 (C ), 140.1 (C ), 139.6 (C ), 130.9 (d, J =
q
q
q
flash chromatography on silica gel (petroleum ether/EtOAc, 8:2 to
:6) to afford 30 (123 mg, 96%) as a beige solid; m.p. Ͼ260 °C. R
q
4
=
f
(CHar), 117.8 (2 CHar), 115.4 (d, J = 21.4 Hz, 2 CHar), 110.1 (C-
1
5) ppm. 19F NMR (376 MHz, [D ]DMSO): δ = –115.87 ppm. IR
0.32 (petroleum ether/EtOAc, 3:7). H NMR (250 MHz, [D
6
]-
6
DMSO): δ = 10.93 (s, 1 H, NH), 8.48 (s, 1 H, 5-H), 7.82 (d, J =
(ATR diamond): ν˜ = 2949, 1597, 1544, 1490, 1456, 1303, 1221, 840,
–
1
7
2
.5 Hz, 2 H, 2 Har), 7.76 (s, 4 H, 4 Har), 7.38 (t, J = 7.5 Hz, 2 H, 736, 707, 659 cm . HRMS (ESI): calcd. for C16
[M + H] 311.07612; found 311.07645.
4
H11FN S
ar), 7.23 (t, J = 7.5 Hz, 1 H, Har) ppm. 13C NMR (101 MHz,
]DMSO): δ = 157.1 (C ), 143.0 (C ), 142.9 (C ), 140.2 (C ),
), 128.6 (2 CHar), 126.7 (CHar), 126.6 (q, J = 3.6 Hz, 2
), 124.2 (2 CHar), 123.1 (C ), 122.3 (d, J = 32.0 Hz,
), 117.6 (2 CHar), 110.4 (C-5) ppm. 1 F NMR (376 MHz, [D
]-
DMSO): δ = –60.09 ppm. IR (ATR diamond): ν˜ = 2794, 1619,
+
H
[D
6
q
q
q
q
6
-(2-Methoxyphenyl)-2-(phenylamine)imidazo[2,1-b][1,3,4]thia-
134.2 (C
q
diazole (35): The reaction was carried out as described in general
procedure B by using the corresponding bromo derivative (100 mg,
CHar), 125.8 (C
C
q
q
9
q
6
0.32 mmol, 1.0 equiv.) and aniline (44 μL, 0.48 mmol, 1.5 equiv.).
–
1
The crude product was purified by flash chromatography on silica
gel (petroleum ether/EtOAc, 7:3) to afford 35 (100 mg, 96%) as a
1
565, 1465, 1320, 1260, 1162, 1105, 1065, 832, 714, 679 cm .
+
11 3 4
HRMS (ESI): calcd. for C17H F N S [M + H] 361.07293; found
pale yellow solid; m.p. 204–206 °C. R
f
= 0.25 (petroleum ether/
]DMSO): δ = 10.50 (s, 1 H,
NH), 8.24 (s, 1 H, 5-H), 8.10 (dd, J = 7.7, 1.8 Hz, 1 H, Har), 7.59
d, J = 7.9 Hz, 2 H, 2 Har), 7.39 (t, J = 7.9 Hz, 2 H, 2 Har), 7.29–
361.07304.
1
EtOAc, 7:3). H NMR (400 MHz, [D
6
2
-(4-Hydroxyphenylamine)-6-phenylimidazo[2,1-b][1,3,4]thiadiazole
(31): The reaction was carried out as described in general procedure
(
B by using the corresponding bromo derivative (100 mg,
7
.15 (m, 1 H, Har), 7.14–7.04 (m, 2 H, 2 Har), 7.01 (d, J = 7.7 Hz,
0
1
.36 mmol, 1.0 equiv.) and 4-hydroxyaniline (36 mg, 0.36 mmol,
.0 equiv.). The crude product was purified by flash chromatog-
13
1
H, Har), 3.94 (s, 3 H, OCH
), 155.4 (C
), 129.2 (2 CHar), 127.4 (CHar), 126.4 (CHar), 122.6 (CHar),
22.5 (C ), 120.4 (CHar), 117.8 (2 CHar), 113.5 (CHar), 111.2 (C-
), 55.3 (OCH ) ppm. IR (ATR diamond): ν˜ = 2834, 1565, 1530,
488, 1465, 1446, 1314, 1250, 1030, 738, 721, 685 cm . HRMS
OS [M + H]+ 323.09611; found
3
) ppm. C NMR (101 MHz, [D
6
]-
DMSO): δ = 157.2 (C
q
q
), 139.7 (C ), 139.2 (C ), 138.4
q
q
raphy on silica gel (petroleum ether/EtOAc, 7:3 to 4:6) to afford 31
90 mg, 81%) as a pale brown solid; m.p. Ͼ260 °C. R = 0.21 (pe-
]DMSO): δ =
0.17 (s, 1 H, NH), 9.31 (s, 1 H, OH), 8.35 (s, 1 H, 5-H), 7.79 (d,
J = 7.2 Hz, 2 H, 2 Har), 7.40–7.31 (m, 4 H, 4 Har), 7.22 (d, J =
(C
q
(
f
1
5
1
q
1
troleum ether/EtOAc, 5:5). H NMR (400 MHz, [D
6
3
1
–1
(
ESI): calcd. for C17
H
14
N
4
.3 Hz, 1 H, Har), 6.79 (d, J = 8.8 Hz, 2 H, 2 Har) ppm. 1 C NMR
101 MHz, [D ]DMSO): δ = 158.3 (C ), 153.3 (C ), 142.5 (C ),
), 134.4 (C ), 131.4 (C ), 128.5 (2 CHar), 126.5 (CHar),
24.1 (2 CHar), 120.3 (2 CHar), 115.6 (2 CHar), 110.1 (C-5) ppm.
3
7
(
1
1
323.09625.
6
q
q
q
40.0 (C
q
q
q
Acknowledgments
IR (ATR diamond): ν˜ = 3131, 3031, 1584, 1514, 1437, 1247, 827,
14, 662 cm–1. HRMS (ESI): calcd. for C16
09.08046; found 309.08089.
12 4
H N
OS [M + H]+
7
3
The authors thank the Ligue Contre le Cancer du Grand Ouest
Comités des Deux Sèvres, du Finistère, de l’Ile et Vilaine, du Loir-
(
2
-[(6-Methoxypyridin-3-yl)amine]-6-phenylimidazo[2,1-b][1,3,4]-
et-Cher, du Loire Atlantique, du Loiret, de la Vienne), the Région
Centre/FEDER (Cosmi programs), the Cancéropôle Grand Ouest
(strand “valorisation des produits de la mer”), and the Ministère
de l’Enseignement Supérieur et de la Recherche (MESR) for their
financial support.
thiadiazole (33): The reaction was carried out as described in gene-
ral procedure B by using the corresponding bromo derivative
(
(
100 mg, 0.36 mmol, 1.0 equiv.) and 6-methoxypyridin-3-amine
28 μL, 0.54 mmol, 1.5 equiv.). The crude product was purified by
Eur. J. Org. Chem. 2015, 6932–6942
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6941

C. Copin, S. Massip, J.-M. Léger, C. Jarry, F. Buron, S. Routier
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Received: July 24, 2015
Published Online: September 29, 2015
6942
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6932–6942