Copper(I)-catalyzed cycloaddition of 4-bromosydnones and alkynes for the regioselective synthesis of 1,4,5-trisubstituted pyrazoles

Article abstract of DOI:10.1021/ol503482a

Copper-catalyzed cycloaddition of alkynes with 4-bromosydnones provides a convenient, mild, and regioselective method for the synthesis of a wide range of bromopyrazoles. The broad functional group tolerance of the cycloaddition reaction and further palla

Full text of DOI:10.1021/ol503482a

Letter
pubs.acs.org/OrgLett
Copper(I)-Catalyzed Cycloaddition of 4‑Bromosydnones and Alkynes
for the Regioselective Synthesis of 1,4,5-Trisubstituted Pyrazoles
Elodie Decuypere, Simon Specklin, Sandra Gabillet, Davide Audisio, Hui Liu, Lucie Plougastel,
Sergii Kolodych, and Frederic Taran*
́
́
CEA, iBiTecS, Service de Chimie Bioorganique et de Marquage, Gif sur Yvette F-91191, France
S
* Supporting Information
ABSTRACT: Copper-catalyzed cycloaddition of alkynes with 4-
bromosydnones provides a convenient, mild, and regioselective
method for the synthesis of a wide range of bromopyrazoles. The
broad functional group tolerance of the cycloaddition reaction and
further palladium-catalyzed cross-coupling reactions allowed the preparation of polyfunctionalized 1,4,5-pyrazoles that are
otherwise difficult to obtain by conventional methods.
Scheme 1. Sydnone Approaches to Trisubstituted Pyrazoles
yrazoles represent a central heterocyclic building block
1
Plargely employed both by the pharmaceutical and the
agrochemical2 industries for the design and synthesis of
biologically active compounds. N-Aryl-polysubstitued pyrazoles
are more particularly present in several FDA-approved
pharmaceutical drugs such as celecoxib (Celebrex), apixaban
(Eliquis), and rimonabant (Acomplia). As a consequence, a
number of efficient synthetic routes to pyrazoles have been
developed.3 Among them, the thermal 1,3-dipolar cycloaddition
reaction of sydnones and alkynes appeared as a promising
approach to construct polysubstituted pyrazoles.4 Sydnones are
stable mesoionic compounds that can react as azomethine
imine-type dipoles with electron-deficient alkynes at elevated
temperatures, giving rise to pyrazoles by CO2 extrusion.5 Harsh
conditions and low regioselectivity have long limited the
interest of this thermal cycloaddition, but some nice examples
of its usefulness for trisubstituted pyrazole synthesis appeared
in the last years. Harrity and co-workers have notably showed
that alkynylboronates undergo cycloaddition reactions with
sydnones in a good regiocontrolled manner leading to 1,3,4-
trisubstitued pyrazole boronic esters, further employed in cross-
coupling Pd-catalyzed reactions (Scheme 1a).6 Several methods
leading to 1,3,5-trisubstitued pyrazoles from 4-halogenosyd-
nones were also developed (Scheme 1b).7 However, these
cycloaddition procedures require elevated temperatures, there-
fore preventing their use on sensitive substrates, and cannot
provide 1,4,5-trisubstituted pyrazoles for which no general and
regiocontrolled synthetic route is available to date.
°C). However, the CuSAC reaction is actually limited to the
synthesis of 1,4-disubstitued pyrazoles. To address this
deficiency, we were interested in exploring the impact of
substitutions in position 4 of the sydnone mesoionic ring on
the CuSAC reaction with the final goal of providing the first
general route to 1,4,5-trisubstituted pyrazoles (Scheme 1c).
Indeed, halogenation on position C-4 of sydnones is easy,10
therefore offering possible functionalization before or after the
cyclization step by Pd-catalyzed-coupling reactions.
A series of C-4-substituted sydnones 1 were therefore
synthesized and reacted with phenylbutyne 2 under standard
CuSAC conditions (Table 1). The results indicated that
substitution at position 4 was globally highly prejudicial to the
reaction, with only the presence of a methyl group dropping the
yield to 7% (compare entries 1 and 2 in Table 1).
Unfortunately, 4-iodosydnones were found to be unstable
Recently, our group has developed a copper(I)-catalyzed
cycloaddition reaction of sydnones with terminal alkynes
(CuSAC)8 which presents similarities with the well-known
copper(I)-catalyzed azide−alkyne cycloaddition reaction
(CuAAC).9 The positive effects of copper catalysis on the
reaction of sydnones with alkynes are numerous: yields are
usually very high, regioselectivity is total and opposite to the
thermal mode, tolerance to chemical and biological functional
groups is almost perfect, and reaction conditions are simple and
mild (organic or aqueous solvents, temperatures from 30 to 60
Received: December 3, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
Table 2). We were then interested in testing diimidazoquinoxa-
lines L9−L12 as new ligands for copper catalysis. These
compounds were described in only two papers for their optical
properties12 but were never used as ligands for catalysis. We
were particularly interested in seeing if the higher angle
between the two coordinative nitrogen atoms, as compared to
phenanthrolines, may have an impact on the catalytic
performances of the corresponding copper complexes. To our
delight, the assays confirmed the anticipated beneficial effect of
these ligands on the reaction (entries 14−17, Table 2).
Although yields and reaction times were only slightly increased,
the main positive effect was observed on the regioselectivity of
the cycloaddition. L11 emerged as the optimum ligand leading
to 5-bromopyrazole 3 as the exclusive product in a good yield
(entry 16, Table 1) and was therefore selected for further
investigations. The ligand effect on this reaction is rather
spectacular: no trace of pyrazole product was observed under
ligand-free conditions (entry 1, Table 2).
With these optimized conditions in hand, we investigated the
scope of the reaction. To simplify the procedure, a one-pot
protocol from sydnones was used to generate 5-bromopyr-
azoles. Bromosydnones were first prepared quantitatively by
electrophilic bromination with N-bromosuccinimide and used
directly without purification in the CuSAC reaction. This
protocol was found to be remarkably tolerant to all tested
functional groups either present on the sydnone or the alkyne
substrates (Scheme 2). Yields were globally good, although low
Table 1. Influence of C-4 Substitution of Sydnones on the
CuSAC Reaction
a
b
entry
R
yield of 3 (%)
3/4
1
2
3
4
5
6
7
8
9
H
98
100/0
100/0
Me
Ph
7
no reaction
no reaction
10
CF3
CN
CHO
Cl
50/50
no reaction
80
96/04
83/17
Br
74
I
traces
a
Experiments were carried at 0.1 M with 1 equiv of reactants, 1 equiv
of triethanolamine, 20 mol % of CuSO4-bathophenanthroline
b
disulfonate (L2) complex, and 2 equiv of sodium ascorbate. isolated
yields.
under the reaction conditions and undergo fast deiodination,
but 4-chloro- and 4-bromosydnones successfully participated in
the CuSAC reaction although regiocontrol was partially lost
(entries 7 and 8, Table 1).
This finding suggests that 1,4,5-trisubstituted pyrazoles may
be obtained through CuSAC reaction with 4-bromosydnones
and further postcyclization functionalization by Pd-catalyzed
coupling reactions. We thus focused our efforts on the
optimization of the reaction with bromosydnones with the
objective of increasing the regioselectivity of the cycloaddition.
We first screened a series of ligands known to modulate the
Cu(I) catalytic activity in the CuAAC reaction.11 Contrary to
what was observed for the CuAAC reaction, tristriazole ligands
L4, L5, and L8 and trisbenzimidazole ligands L6 and L7 were
found to be surprisingly less efficient than bathophenanthroline
L2 (compare entry 4 with entries 7, 9, and 11−13 in Table 2),
suggesting that bidentate ligands form more active copper
complexes for CuSAC than tridentate ones. Increasing the
temperature to 100 °C was also prejudicial to the reaction
efficiency and induced the formation of the debrominated
byproduct 5 (compare entries 5, 8, and 10 with 4, 7, and 9 in
Scheme 2. Scope of the Reaction (Isolated Yields)
a
Table 2. Optimization of the Reaction Conditions
b
c
entry
ligand
temp (°C)
yield of 3 (%)
3/4/5
d
1
none
L1
100
60
n.d.
2
67
54
74
42
n.d.
16
65
32
45
n.d.
n.d.
27
60
13
75
74
83/10/07
84/16/0
83/17/0
36/03/61
3
L2
25
4
L2
60
5
L2
100
100
60
6
L3
7
L4
97/03/0
86/03/11
92/08/0
78/06/16
8
L4
100
60
9
L5
10
11
12
13
14
15
16
17
L5
100
100
100
100
60
L6
L7
L8
97/0/03
97/0/03
100/0/0
100/0/0
100/0/0
conversions of the bromosydnone substrates 3f, 3i, and 3l were
observed. In all cases, crude reactions were clean, with no traces
of regioisomer or debromination byproducts.
We then tried to extend this approach to the preparation of
1,4,5-trisubstitued pyrazoles by using the formed 5-bromopyr-
azoles in Pd-catalyzed cross-coupling reactions with appropriate
boronic acids. As with many N-heterocyclic substrates,
pyrazoles have the reputation of being poor substrates for the
L9
L10
L11
L12
60
60
60
a
b
Experiments were carried at 0.1 M with 1 equiv of reactants. Isolated
c
d
1
yields. Ratios determined by H NMR and HPLC. 62% yield of
debrominated 1 was isolated.
B
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Organic Letters
Letter
Suzuki reaction.13 To our knowledge, no Suzuki coupling on N-
aryl-5-bromopyrazole 3 has been described so far in the
literature. We thus performed a screening of a series of Pd
sources (Table S1, Supporting Information) and identified 1,1′-
bis(di-tert-butylphosphino)ferrocene palladium dichloride (Pd-
(dbpf)Cl2)14 as the most efficient catalyst (Scheme 3). With
Scheme 5. Proposed Mechanism
Scheme 3. Preparation of 1,4,5-Pyrazoles 6
provoking nucleophilic attack at C-4 by the β-carbon of the
acetylide to form intermediate II. This step creates a covalent
C−C bond and is highly sensitive to both steric and electronic
effects of the R′ substituent as illustrated by the results in Table
1. Bulky moieties or electron-withdrawing groups, which
decrease the nucleophilicity of N-2, are prejudicial to the
reaction. Ring closure and decarboxylative retro-Diels−Alder
reaction then afford pyrozolide IV. Protonolysis then completes
the cycle, liberating pyrazole 3 and regenerating the copper
catalyst.
In conclusion, we described a stepwise copper and palladium-
catalyzed route to 1,4,5-trisubstitued pyrazoles. This synthetic
approach is the first to permit complete control over the
placement of substituents in positions 1, 4, and 5 of the
pyrazole core and therefore would be a valuable addition to
known pyrazole construction approaches and would aid the
search for new bioactive pyrazoles. The copper-catalyzed
cycloaddition reaction of bromosydnones with alkynes, which
display high functional group compatibility and excellent
chemo- and regioselectivities, is the key step of the process.
Imidazoquinoxalines have been used for the first time as new
bidentate ligands for copper catalysis and proved to be highly
beneficial to the CuSAC reaction. We think these compounds
may find broad applications as transition-metal ligands in the
future.
this catalyst, aryl-, styryl-, and alkylboronates proceeded
smoothly in Suzuki coupling with 5-bromopyrazole 3b, and
the procedure was found to be compatible with the more
functionalized bromopyrazoles 3j, 3p, and 3n.
Sydnones are known to share common features with N-
heterocyclic carbenes15 and to form stable complexes with
transition metals,16 including copper,17 by forming a carbon−
metal bond in position 4 of the mesoionic ring under basic
conditions. The fact that 4-methyl-, 4-chloro-, and 4-
bromosydnones are substrates for the CuSAC reaction (see
Table 1) does not account for a carbene-like process. The
mechanism is more likely to proceed through coordination of
the nitrogen atom in position 2 of sydnones by classical
copper(I) acetylide species. Furthermore, when the reaction is
performed in deuterated solvent, labeling occurs in position 3
of the pyrazole ring (Scheme 4) starting both from sydnone or
ASSOCIATED CONTENT
* Supporting Information
■
S
Scheme 4. Mechanistic Investigation
Experimental details and characterization data of all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: frederic.taran@cea.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the French National Agency (ANR, ClickScreen
project) for financial support.
bromosydnone, which is in agreement with deprotonation of
the starting alkyne by copper and deuterolysis of the carbon−
copper bond of a 3-cuprated pyrazole intermediate.
■
Based on these experiments and on the established
mechanism of the CuAAC reaction,18 we suggest the
mechanistic proposal outlined in Scheme 5. First, the in situ
formed copper−acetylide species I reversibly coordinates the
N-2 atom of the dipolar resonance form 1 of the sydnone,
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