Palladium-Catalyzed Amination of C-5 Bromoimidazo[2,1-b][1,3,4]thiadiazoles

Article abstract of DOI:10.1002/ejoc.201600145

A new and efficient palladium-catalyzed amination of imidazo[2,1-b][1,3,4]thiadiazole at the C-5 position under microwave irradiation is reported. The reactivity toward bromine release at the C-5 position was investigated, and palladium-catalyzed cross-co

Full text of DOI:10.1002/ejoc.201600145

DOI: 10.1002/ejoc.201600145
Communication
Heterocycles
Palladium-Catalyzed Amination of C-5 Bromoimidazo[2,1-b]-
[1,3,4]thiadiazoles
Chloé Copin,[a] Frédéric Buron,[a] and Sylvain Routier*[a]
Abstract: A new and efficient palladium-catalyzed amination range of amines was employed to examine the scope and limi-
of imidazo[2,1-b][1,3,4]thiadiazole at the C-5 position under
microwave irradiation is reported. The reactivity toward brom-
ine release at the C-5 position was investigated, and palladium-
catalyzed cross-coupling conditions were optimized. A wide
tations of the method. To complete this methodological study,
the influence of the nature and the positions of additional imid-
azo[2,1-b][1,3,4]thiadiazole substitutions was investigated.
Introduction
dem sequence including bromination and halogen displace-
ment under Buchwald–Hartwig cross-coupling strategies[10,12]
to synthesize compounds of type I (Scheme 1). We proved the
versatility of the approach and its efficiency toward primary or
secondary benzyl, alkyl, aromatic, and heteroaromatic amines
in the presence of various C-2 and C-6 substituents.
In the last few years, imidazo[2,1-b][1,3,4]thiadiazole, a bicyclic
[5-5]-fused system with one bridgehead nitrogen atom, has
been widely used to design many bioactive compounds.[1] This
scaffold has proven applicable to the discovery of a wide variety
of biologically active molecules and antitumor,[2] antitubercu-
lar,[3] and analgesic agents.[4]
Current strategies for preparing imidazo[2,1-b][1,3,4]thiadi-
azole derivatives generally consist of building imidazothiadi-
azole by condensation of 2-amino-5-substituted[1,3,4]thiadi-
azoles with various α-haloketones or acetophenones.[5] Al-
though compounds with well-positioned substituents are ob-
tained, the major limitations of these strategies are the neces-
sity of unavailable polyfunctionalized reagents and harsh condi-
tions. These drawbacks constitute a major hindrance to the de-
velopment of medicinal chemistry programs or exploration of
the corresponding chemical space. It is therefore of interest to
propose alternative methods.
Scheme 1. C-5 amination program.
Results and Discussion
For several years, our group has been developing efficient
methodologies to selectively functionalize heterocycles such as
azaindoles,[6] pyridopyrimidines,[7] and, more recently, bicyclic
heterocycles that have two five-membered fused rings, such as
triazolothiadiazoles,[8] thiazolotriazoles,[9] or imidazothiadi-
azoles.[10] In the latter series, our latest challenge is to directly
access a variety of original C-5-aminated compounds. To the
best of our knowledge, the sole route for the synthesis of C-
5-aminated imidazo[2,1-b][1,3,4]thiadiazoles consists of using a
three-component Groebke–Blackburn–Bienaymé reaction.[11]
However, only secondary amines are generated by using this
strategy with the chosen isocyanide. This paper reports a tan-
First, 5-bromoimidazo[2,1-b][1,3,4]thiadiazole derivatives 11–20
were prepared by using a two-step cyclization/bromination se-
quence involving commercially available 2-amino-5-methyl or
5-aryl[1,3,4]thiadiazoles and a variety of α-halogenoketones in
boiling ethanol (Table 1).[13] At the C-2 and C-6 positions,
methyl or phenyl systems with or without electron-donating or
electron-withdrawing groups were used. At the C-6 position, we
additionally prepared hydrogenated derivative 1 and ethyl ester
2. Cyclization step 1 and bromination step 2 occurred smoothly
in most cases. Obtaining 1 and its bromination remained diffi-
cult even if step 2 appeared to be fully regioselective. Bromina-
tion of 4 and 5 led to polyhalogenated derivatives. Fortunately,
derivatives 14 and 15 could be separated from the complex
mixture. This representative C-5 bromoimidazothiadiazole li-
brary (Table 1) contains enough diversity to find general condi-
tions during amination studies.
[a] Institut de Chimie Organique et Analytique (ICOA),
Université d'Orléans, CNRS UMR 7311,
45067 Orléans, France
E-mail: sylvain.routier@univ-orleans.fr
http://www.icoa.fr/fr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600145.
At the beginning of this study, we tried the simple displace-
ment of the C-5 bromine atom under SNAr conditions, but all
attempts remained unsuccessful, regardless of the temperature
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Table 1. Synthesis of type I derivatives and their C-5 brominated analogs.
[a] Yields are indicated for isolated compounds.
and the activation mode (thermal or microwave irradiation) failed and only starting material was recovered (Table 2, entry
used. This lack of reactivity prompted us to quickly switch to 1). However, increasing the amount of base, the catalytic sys-
palladium-catalyzed reactions (Table 2).
tem, as well as the reaction time and temperature, partially re-
stored the reactivity, and the desired compound 21 was formed
We started with conditions that had proved their efficiency
in the imidazotriazole series,[14] but in this case, all attempts in an encouraging 11 % yield (entry 2).
Table 2. Optimization of the palladium-catalyzed reaction to synthesize 21.
Entry
Pd2dba3
Xantphos
Base
Solvent, Heating, Temp., Time
Yield of 21[a]
1
2
3
4
5
6
7
8
5.0 mol-%
10.0 mol-%
10.0 mol-%
5.0 mol-%
2.5 mol-%
5.0 mol-%
5.0 mol-%
–
10.0 mol-%
20.0 mol-%
20.0 mol-%
10.0 mol-%
5.0 mol-%
10.0 mol-%
10.0 mol-%
10.0 mol-%
K2CO3 (2.0 equiv.)
K2CO3 (3.0 equiv.)
Cs2CO3 (3.0 equiv.)
Cs2CO3 (3.0 equiv.)
Cs2CO3 (3.0 equiv.)
Cs2CO3 (3.0 equiv.)
Cs2CO3 (3.0 equiv.)
Cs2CO3 (3.0 equiv.)
Dioxane, μW, 130 °C, 15 min
Dioxane, μW, 140 °C, 30 min
Dioxane, μW, 140 °C, 30 min
Dioxane, μW, 140 °C, 30 min
Dioxane, μW, 140 °C, 30 min
DME, μW, 140 °C, 30 min
ND[b]
11 %
91 %
92 %
87 %
86 %
34 %
ND[b]
Toluene, μW, 140 °C, 30 min
Dioxane, μW, 140 °C, 30 min
[a] Yields are indicated for isolated compounds. [b] ND: not detected, only starting material was recovered.
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The nature of the base was investigated next. Surprisingly, impact of steric effects (entries 3, 4). 3,5-Dichloroaniline re-
Cs2CO3 led to a full conversion in only 30 min, and the targeted mained suitable for the synthesis of 25, which was again ob-
product 21 was isolated in a very good yield of 91 % (entry 3). tained in a very good yield (entry 5).
A further catalyst charge adjustment to 5.0 mol-% proved to be
a good compromise as 2.5 mol-% led to a slight decrease in
the yield (entries 4, 5). It is noteworthy that all attempts to
change the solvent led to a decrease in yield (entries 6–7), and
DMF imparted a strong instability to the catalytic system, which
quickly stopped working. Finally, suppression of the catalyst
(entry 8) confirmed that the amine introduction is due to a
Buchwald type reaction and not by an SNAr pathway.
To prove the usefulness of this novel cross-coupling reaction,
we then studied the reactivity of 13, which was prepared on
a large scale with a representative aminated derivative panel
(Table 3). While aniline gave satisfactory yields, anisidine and 4-
There appeared to be an electronic dependence of the amin-
ation given the condensation of the 4-CF3 aniline or 3-amino-
pyridine, which led to 26 in only 49 % yield, while 27 was never
detected (entries 6, 7). To confirm this hypothesis, we used the
2-OMe-5-aminopyridine. The addition of an electron-donating
group restored the reactivity, and 28 was isolated in a 65 %
yield (entries 7, 8). Finally, the amination was not efficient with
lactams or primary aliphatic amines, but the condensation of
bromo derivative 13 with the morpholine, a highly reactive
cyclic secondary amine, led to the desired product 32 in moder-
ate yield (entry 12).
To study the scope and limitation of this reaction, we then
aminophenol were less efficient (entries 2, 3). Isomerization of investigated the influence of the nature of the C-6 and C-2 sub-
the OMe group to the ortho position did not interfere with the stituents on the efficiency of the reaction with aniline as partner
efficiency of the reaction. This result seems to indicate the low (Table 4). A sensitive but less bulky ester substituent at position
Table 3. Library of aminated compounds 21–32.
[a] Yields are indicated for isolated compounds. [b] ND: not detected.
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Table 4. Synthesis of compounds 21, 33–41.
[a] Yields are indicated for isolated compounds. [b] ND: not detected, only starting material was recovered. [c] Detected by 1H NMR spectroscopy.
C-6 was fully compatible with the palladium-catalyzed reaction, palladium-catalyzed system was optimized. An efficient, low-
and 34 was isolated in an excellent 95 % yield (entry 2).
When the bromothiadiazole derivative was substituted by a
methyl group at the C-2 position and an aryl group at the C-6
position, the reaction gave trisubstituted derivatives 21, 35, and
37 in satisfying yields (entries 3, 4, 6). Nevertheless, the absence
of a C-6 substituent or inversion of the substituent positions
(i.e. aryl at C-2 and methyl at C-6) led to inactivation of the
system (entries 1, 10). The real sensitivity to the presence of a
labile proton is shown by the results obtained for derivatives
36 and 37 (entries 5, 6).
catalyst-loading procedure was employed under microwave-as-
sisted activation and gave the desired C-5 aminated derivatives.
The nature and the positions of additional imidazothiadiazole
substitutions or aniline derivatives had a great influence on the
efficiency. In contrast to the other reported strategies, this syn-
thesis enabled the easy introduction of aniline derivatives or
secondary amines at the C-5 position. We are currently design-
ing these scaffolds in order to synthesize new biologically active
compounds.
No reaction occurred in the presence of a phenol derivative,
whereas oxygen methylation restored the reactivity and 37 was
isolated in a satisfying yield. Finally, when two aryl groups were
placed at the C-2 and C-6 positions, the desired products were
obtained in good yields (entries 7–9), albeit with a slightly lower
yield of isolated product 40 because of the purification step.
Experimental Section
Supporting Information (see footnote on the first page of this
article): Detailed experimental procedures, characterization data,
and spectra of the compounds.
Acknowledgments
The authors thank the Ligue Contre le Cancer du Grand Ouest
(Comités des Deux Sèvres, du Finistère, de l'Ile et Vilaine, du
Loir-et-Cher, du Loire Atlantique, du Loiret, de la Vienne), the
Conclusions
This study offers chemists an alternative and more practical Région Centre (Cosmi FEDER program including labex Iron and
method to directly introduce aminated groups at the C-5 posi- SYNORG), the Cancéropôle du Grand Ouest (strand “valorisation
tion in the imidazo[2,1-b][1,3,4]thiadiazole series. The Buch- des produits de la mer”), and the Ministère de l'Enseignement
wald–Hartwig cross-coupling reaction was performed, and the Supérieur et de la Recherche (MESR) for their financial support.
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Keywords: Nitrogen heterocycles · Sulfur heterocycles ·
Amination · Cross-coupling · Palladium
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Received: February 9, 2016
Published Online: April 5, 2016
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