Efficient synthesis and first regioselective c-3 direct arylation of imidazo[1,2-b]pyrazoles

Article abstract of DOI:10.1002/chem.201202593

Highly regioselective: An efficient synthesis of the imidazo[1,2-b]pyrazole core has been developed, and the first regioselective palladium-catalyzed direct arylation of the C-3 position is described (see scheme). Good to excellent yields were obtained for a wide range of aryl partners with electron-rich and electron-poor substituents. This methodology allows rapid access to a large variety of imidazo[1,2-b]pyrazole products and could open the way to the design of new biologically active compounds. Copyright

Full text of DOI:10.1002/chem.201202593

COMMUNICATION
DOI: 10.1002/chem.201202593
Efficient Synthesis and First Regioselective C-3 Direct Arylation of
ImidazoACTHUNRTGNEUNG[1,2-b]pyrazoles
Sandrine Grosse,[a] Christelle Pillard,[b] Stꢀphane Massip,[c] Jean Michel Lꢀger,[c]
Christian Jarry,[c] Stꢀphane Bourg,[a, d] Philippe Bernard,[b] and Gꢀrald Guillaumet*[a]
In recent years, 5,5-fused ring systems have attracted
much attention. Such systems that contain three nitrogen
atoms are found in compounds showing a wide range of bio-
Table 1. Preparation of imidazoACTHUNGETRNNU[G 1,2-b]pyrazoles 5a–c.
logical activities. For example, imidazoACTHNUTRGENUG[N 1,2-b]pyrazoles have
been designed, prepared, and studied as anticancer,[1] anti-
fungal,[2] and anti-inflammatory agents[3] or for the treat-
ment of neurodegenerative disorders.[4]
Current strategies for preparing substituted imidazoACHTUNTRGNEUNG[1,2-
b]pyrazole derivatives generally consist in constructing the
5,5-fused ring with the desired substituents in appropriate
position.[1a,b,2b,5] Only few methods of direct functionaliza-
tion of the heterocyclic moiety have been described. In this
context, the overall goal of our research was to develop an
efficient synthesis of the imidazo
that permits its subsequent functionalization, thereby en-
abling molecular diversity.
We started our investigations by using the commercially
ACHTUNGERTN[NUNG 1,2-b]pyrazole synthon
ACHTUNGTRENNUNG
Entry
R
Step A [%][a]
Step B [%][a]
Step C [%][a]
available 3(5)-phenyl-1H-pyrazol-5(3)-amine (1), which was
selectively N-alkylated with various a-bromoacetophenones
2a–c in acetonitrile under basic conditions in moderate
yields (Table 1).
1
2
3
OCH3
CF3
CH3
40 (3a)
48 (3b)
57 (3c)
98 (4a)
90 (4b)
93 (4c)
65 (5a)
60 (5b)
61 (5c)
26 (6a)
17 (6b)
16 (6c)
[a] Isolated yields.
Optimization procedures were assessed, that is, base, sol-
vent, temperature, and reaction time, but no significant im-
provement was observed. The regioselectivity of the N-al
kylation was established by a single-crystal X-ray study of
the pyrazole 3a (see the Supporting Information). Cycliza-
tion of 3a–c under acidic conditions in ethanol afforded
imidazopyrazoles 4a–c as chlorohydrates in high yields.
Compound 4 was N-methylated by using iodomethane in
the presence of sodium hydride in N,N-dimethylformamide,
which afforded two products in good overall yields (77 to
91%): the N-methylated product 5 and the N- and C-3-
[a] S. Grosse, Dr. S. Bourg, Prof. G. Guillaumet
Institut de Chimie Organique et Analytique (ICOA)
Universitꢀ d’Orlꢀans
methACTHNUTRGENUyGN lated compound 6 in a 73:27 to 86:14 ratio. These
structures were confirmed by single-crystal X-ray studies
(see the Supporting Information). To minimize the forma-
tion of product 6, different bases (KH, KOH, Na2CO3,
K2CO3, Cs2CO3, Ag2CO3, nBuLi), a different methylating
UMR-CNRS 7311, BP 6759, rue de Chartres
45067 Orlꢀans cedex 2 (France)
Fax : (+33) 38 41 72 81
E-mail: gerald.guillaumet@univ-orleans.fr
[b] Dr. C. Pillard, Dr. P. Bernard
Greenpharma S.A.S, 3, allꢀe du Titane
45100 Orlꢀans (France)
agent (dimethylACTHNUTRGNEUNGsulfate), or different solvents (DMF, THF,
acetone)[6] were tested. Nevertheless, in each case, either the
two compounds were obtained in lower yields or the reac-
tion afforded degradation products. Regarding the 5,5-fused
[c] Dr. S. Massip, Prof. J. M. Lꢀger, Prof. C. Jarry
Universitꢀ Bordeaux, CNRS FRE 3396, Pharmacochimie
146 Rue Lꢀo Saignat, 33000 Bordeaux (France)
ring systems, two positions of the imidazoACTHNUGRTENUNG[1,2-b]pyrazole
[d] Dr. S. Bourg
core remain potentially functionalizable, enlarging the po-
tential molecular diversity offered by this synthon.
Centre de Biophysique Molꢀculaire UPR-CNRS 4301
Rue Charles Sadron, 45071 Orlꢀans cedex 2 (France)
À
In recent years, the direct C H arylation of aromatic and
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202593. It contains experi-
mental procedures, full spectroscopic data, DFT studies, and crystal-
lographic data for all new compounds.
heteroaromatic compounds has emerged as an attractive al-
ternative method to the more classic cross-coupling re-
AHCTUNGTRENNUNG
actions.[7] In contrast to palladium-catalyzed couplings, such
Chem. Eur. J. 2012, 18, 14943 – 14947
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
14943

as Suzuki, Stille, or Negishi couplings, which require the
preparation of organometallic reagents (boronic acids, tin,
or zinc derivatives), preliminary functionalization is avoided
À
in direct C H arylation. As a result, the number of steps,
waste, and solvent and the reaction time are usually re-
À
duced. As part of our research effort in direct C H aryla-
tion,[8] we set out to explore the C-3 and C-7 reactivity of 5a
À
toward C H arylation. Notably, arylation of electron-poor
heterocycles, in particular five-membered heterocycles con-
taining two or three hetero
ACHTUNGTRNEaNUNG toms, is the most intriguing chal-
lenge in this field today.[9] To the best of our knowledge, no
Figure 1. ORTEP representation of 7a.
example of direct arylation of the imidazo
core has been reported.
ACHTUNGTREN[NGNU 1,2-b]pyrazole
The Pd0-mediated arylation of 5a by using 4-bromo
toluene as the coupling partner under thermal heating af-
forded the desired C-3-arylated imidazopyrazole 7a, but in
a mixture with 8 (Table 2, entry 1). This by-product resulted
from the insertion of the phenyl group of triphenylphos-
phine in C-3. This reactivity is quite rare, but has been re-
creased the quantity of arylbromide (entry 4) or replaced
potassium carbonate by caesium carbonate (entry 8). In
both cases, the arylation of C-3 and C-7 took place, giving
rise to an inseparable mixture of 7a and 9 (entries 4 and 8).
While using a protic solvent decreased the yield to 20%
(entry 5), the replacement of toluene by 1,4-dioxane gave a
better result (entry 7). Finally,
the optimal reaction conditions
were found to be imidazopyr-
Table 2. Pd-catalyzed regioselective C-3 arylation of 5a.[a]
AHCTUNGTERGaNNUN zole 5a (1.0 equiv), 4-bromo
toluene (1.0 equiv), palladium
acetate (10 mol%), tricyclohex-
ylphosphine (20 mol%), and
potassium carbonate (2.0 equiv)
in 1,4-dioxane, heated for
1
hour at 1608C under microwave
irradiation (entry 9).
We tried to understand the
origin of this regioselectivity,
which is the real challenge in
Entry Ligand Base
p-Me-C6H4-Br Solvent
[equiv]
Heating
system
t
Ratio
Yield
[%][c]
AHCTUNGTRENNUNG
[h] 7a/8/9[b]
1
2
3
4
5
6
7
8
9
PPh3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
1.5
1.0
1.0
1.5
1.0
1.0
1.0
toluene
toluene
toluene
toluene
reflux
reflux
MW, 1608C
MW, 1608C
MW, 1608C
15
41
4
64:36:0 81[d]
À
100:0:0
100:0:0
70
80
direct C H arylation studies
today.[12] Several mechanistic
scenarios have been proposed
to explain palladium-catalyzed
direct-arylation outcomes, in-
cluding SEAr, Heck-like addi-
tion, and a CMD (concerted
metalation–deprotonation)
mechanism.[13]
4
4
4
4
4
1
89:0:11 91[d]
toluene/EtOH 2:1
1,4-dioxane/EtOH 2:1 MW, 1608C
1,4-dioxane
1,4-dioxane
1,4-dioxane
100:0:0
100:0:0
100:0:0
95:0:5
20
14
MW, 1608C
MW, 1608C
MW, 1608C
83
Cs2CO3 1.0
K2CO3 1.0
75[d]
86
100:0:0
[a] The reactions were carried out with 5a (0.329 mmol), 4-bromotoluene (specified quantities), palladium ace-
tate (10 mol%), ligand (20 mol%), and base (2.0 equiv) in solvent (2 mL). [b] 1H NMR ratio based on the in-
tegration of H-7 or OCH3. [c] Isolated yields after column chromatography. [d] Mixture of inseparable prod-
ucts after column chromatography of the crude mixture.
To identify the role that the
À
C H bond acidity plays in the
site selectivity of this re
A
ported already.[10] Thus, we replaced triphenylphosphine by
tricyclohexylphosphine (PCy3), which allowed us to isolate
7a as a single product in a good 70% yield (entry 2). Spec-
tral data (NOESY correlations between H-7 and NCH3)
were in accordance with structure 7a. In addition, the com-
plete regioselectivity on C-3 was confirmed by a single-crys-
deuterium-incorporation experiments were carried out.
Deuterium exchange of imidazo[1,2-b]pyrazole 5a by treat-
ment with KOH in a mixture of dioxane and D2O reveals
that the C-3 site exchanges exclusively,[14] which shows that
C-3 is by far the most acidic position (Scheme 1). A plausi-
AHCTUNGTRENNUNG
À
ble mechanism for this C H arylation, generally linked to
A
acidity, is a CMD pathway proposed by Fagnou and co-
workers.[13g, 15]
crystallizes in two polymorphic forms (for details, see the
Supporting Information).
To improve the reaction yield, we first used microwave ir-
radiation,[11] which increased the yield to 80% and signifi-
cantly reduced the reaction time (entry 3). We then in-
To explore the scope of the methodology and detect pos-
sible limitations, we applied these selected conditions to the
three imidazo
ACHTUNGTRENUN[NG 1,2-b]pyrazoles 5a–c by choosing various
hetero(aryl) bromides (Table 3). Hence, we could first ob-
AHCTUNGTRENNUNG
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Chem. Eur. J. 2012, 18, 14943 – 14947

Synthesis and Arylation of ImidazoACTHNUTRGNE[NUG 1,2-b]pyrazoles
COMMUNICATION
Table 3. Scope of the Pd-catalyzed C-3 arylation of 5a–c.[a]
Scheme 1. Deuterium incorporation of 5a.
À
serve that the C H arylation on C-3 is not influenced by the
nature of the group in C-2 position. Then, it was noticed
that aryl bromides that bear a variety of functional groups
were well tolerated. More specifically, aryl bromides con-
taining electron-withdrawing (CN, COOCH3, CF3) or elec-
tron-donating groups (CH3, OCH3) gave C-3-arylated
imidazoACHTUNGTRENNUNG[1,2-b]pyrazoles in excellent yields. Steric hindrance
did not significantly influence the yield, except in the case
of 2-cyanophenylbromide for which the yield dropped to
60%.
To enlarge the scope of the method, some heteroaryl bro-
mides were also tested. The use of 3-bromothiophene and
3-bromofurane led to incomplete conversion and the desired
products in 24 and 18% yield, respectively. No improvement
was observed by increasing the reaction time. Since Fag-
nouꢂs group described a palladium–pivalic acid combination
À
for the C H arylation of aromatic heterocycles that exhibit-
ed unprecendented reactivity,[16] pivalic acid was added as
cocatalyst. In this case, no particular improvement in re-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
We also extended the methodology to aryl or heteroaryl
chlorides, which are often, but not always, less expensive
and more readily available than the corresponding bromides
and iodides.[17] Remarkably, our conditions could be success-
fully applied to electron-rich, electron-poor, or heteroaryl
chlorides, although they are known to be less reactive (see
Table 3, footnote [b]). The compatibility of the strategy with
both chlorides and bromides as coupling partners suggests
the possibility of introducing a larger range of groups.
Then, arylation of the NH-imidazopyrazole 4a (Table 4)
was carried out. Direct arylation under optimized conditions
afforded compound 10 as a single product with 40% yield
(entry 1). To confirm the regioselectivity of the reaction, 10
was subjected to a methylation reaction by using iodo-
[a] Isolated yields after column chromatography. [b] The reaction was
performed by using (hetero)aryl chloride instead of (hetero)aryl bromide.
[c] 75% of starting material recovered. [d] 80% of starting material re-
covered.
ACHTUNGTRENNUNGmethane and sodium hydride in N,N-dimethylformamide
(Scheme 2). All the spectral data of the resulting product
were in perfect agreement with those of compound 7a,
À
which confirms a direct C H arylation in C-3 position for
the free NH-imidazopyrazole 4a.
rapid degradation at room temperature, which forced us to
keep the product at À208C. Consequently, imidazopyrazole
10 was transformed into the corresponding hydrochloride
salt 11 (Scheme 2), which is more stable and allows a longer
storage.
Optimization of the procedure was carried out, for exam-
ple, by changing the base, solvent, or ligand or by adding an
additive, such as pivalic acid. Unfortunately, the yield never
exceeded 40%, presumably owing to the presence of the
À
free NH group, which may disfavor C H arylation. In addi-
tion, we noted a poor stability of 10. Indeed, we observed its
In summary, we developed a novel and efficient synthesis
of the imidazoACTHUGNETRNNU[G 1,2-b]pyrazole core. Then, a palladium-cata-
Chem. Eur. J. 2012, 18, 14943 – 14947
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
14945

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Ligand
Base
p-Me-C6H4Br
[equiv]
Solvent
t
Yield
[Chem. Abstr. 1996, 124, 8700].
G
[h]
[%][a]
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1
2
3
4
5
PCy3
PCy3
PCy3
PCy3
PCy3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
1.0
1.5
1.5
1.5
1.5
1,4-dioxane
1,4-dioxane
1,4-dioxane
toluene
toluene/EtOH
2:1
4
4
4
4
40
41
38[b]
31
[c]
0.5
–
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[c]
6
7
PCy3
Xts[d]
Cs2CO3
K2CO3
1.5
1.5
toluene
toluene
4
4
–
–
[c]
[a] Isolated yields after column chromatography. [b] The reaction was performed with
pivalic acid (0.30 equiv). [c] Degradation. [d] Xts=Xantphos.
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and b) structure confirmation by N-methylation. [a] Isolated yields.
À
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highly selective C-3 direct arylation. Good to excellent
yields were obtained for a wide range of aryl coupling part-
ners with both electron-rich and electron-poor substituents,
giving access to a library of diverse imidazoACTHNUGRTENUNG[1,2-b]pyrazole
compounds. Further studies are currently in progress in our
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Acknowledgements
This work has been supported by Greenpharma Society and the Conseil
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À
Keywords: arylation · C C coupling · fused-ring systems ·
microwave chemistry · palladium · regioselectivity
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Synthesis and Arylation of ImidazoACTHNUTRGNE[NUG 1,2-b]pyrazoles
COMMUNICATION
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Received: July 23, 2012
Revised: September 7, 2012
Published online: October 19, 2012
Chem. Eur. J. 2012, 18, 14943 – 14947
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
14947