Cu-catalysed pyrazole synthesis in continuous flow

Article abstract of DOI:10.1039/c5cy02247a

The synthesis of 1,4-disubstituted pyrazoles via the cycloaddition reaction of sydnones and terminal alkynes has been achieved employing silica-supported copper catalysts. Furthermore, this methodology has been successfully implemented in continuous flow

Full text of DOI:10.1039/c5cy02247a

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Cu-Catalysed Pyrazole Synthesis in Continuous Flow
a
b
c
Júlia Comas-Barceló , Daniel Blanco-Ania , Sebastiaan A. M. W. van den Broek , Pieter J.
c
a,*
b,*
Received 00th January 20xx,
Accepted 00th January 20xx
Nieuwland , Joseph P. A. Harrity and Floris P. J. T. Rutjes
The synthesis of 1,4-disubstituted pyrazoles via the cycloaddition reaction of sydnones and terminal alkynes has been
achieved employing silica-supported copper catalysts. Furthermore, this methodology has been successfully implemented
in continuous flow conditions using prepacked stainless steel cartridges containing the solid-supported copper promoter.
Finally, we demonstrate that this synthetic procedure can be successfully scaled up to produce practically useful amounts
of pyrazole products within 2-5 hours.
DOI: 10.1039/x0xx00000x
www.rsc.org/
reduction of Cu(II) to Cu(I), thereby facilitating the formation
of a reactive Cu-acetylide intermediate. In addition to these
Introduction
1
,2
drawbacks, copper acetylides are known to be extremely
Pyrazoles are commonly found in pharmaceuticals
and
1
3
3
insoluble and tend to form aggregates. This reduces the
concentration of active reagent in solution, thus reducing the
reaction rate and causes problems with mixing on larger scale
agrochemicals, and straightforward methods for their
synthesis serve to underpin both the discovery of active
compounds and their preparation on larger scale. Among the
many synthetic approaches to these heterocycles, dipolar
cycloadditions offer a convenient means to access complex
pyrazoles from simple substrates, and this approach is widely
1
4,13
as the formation of thick slurries is often observed.
We envisaged that flow chemistry could provide an
effective approach to address the most critical issues
encountered in the copper(II) acetate-promoted cycloaddition
of alkynes and sydnones. Specifically, moving from a batch
process to the use of supported catalysts in a continuous flow
apparatus seemed a feasible solution to addressing the
formation of slurries. In this regard, Ley and co-workers have
already shown that mechanical stirring employing agitating cell
reactor (ACR) devices can successfully avoid clogging of the
4
used.
In this context, we have had a long standing interest in the
employment of cycloaddition reactions of alkynes and
5
,6,7
sydnones for pyrazole synthesis.
typically require high reaction temperatures (typically 160-180
C) and long reaction times. Moreover, reaction regiocontrol
However, these reactions
°
can raise challenges and many unsymmetrical alkynes
generate regioisomeric mixtures, which is the case for e.g.
1
5
flow system, among other strategies.
8
9
The use of supported catalysts for the promotion of dipolar
cycloadditions has not been extensively reported outside of
the established ‘click’ reaction of alkynes and azides to
generate triazoles. In this latter case however, several
different supported forms of copper have been shown to
successfully promote the reaction both in batch and in flow.
ethyl propiolate and 2-ethynylpyridine. Recently however,
Taran et al. have devised a copper-catalysed cycloaddition of
terminal alkynes that proceeds under milder conditions (60 °C,
1
0,11,12
16 h) and with excellent regiocontrol.
In addition, we
have reported the copper(II) acetate-promoted cycloaddition
between sydnones and terminal alkynes that provides access
1
6
8
For example, Cu(0) powder, CuI supported on Amberlyst® A-
to 1,4-disubstituted pyrazoles in a regioselective manner.
1
1, and both Cu(I) and Cu(II) salts supported on amino-
7
2
Although this reaction generates 1,4-disubstituted isomers
with excellent regiocontrol and using the readily available
copper(II) acetate, it requires stoichiometric amounts of
copper and two equivalents of the alkyne substrate. We
reasoned that the excess alkyne was required to mediate the
1
8,19,20
modified silica, have all proved to be effective.
McQuade
has also reported the use of Cu
2
O suspended in 4Å molecular
sieves for the generation of N-heterocyclic carbene
2
1
complexes. As an alternative strategy, reactors made of
copper metal have been developed that promote dipolar
cycloadditions and other copper-catalysed processes such as
Sonogashira cross couplings or Ullman-type reactions. In these
cases the addition of extra catalyst is no longer necessary, thus
2
2
reducing the levels of complexity of the system. An example
of this has been reported by Sach, where the synthesis of
1,2,3-triazoles under flow conditions is carried out by means of
copper-made disquette reactors in the absence of extra
23
copper sources.
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Table 1. Copper loadings for the supported catalysts prepared.
Entry
Matrix
Silica-1
Silica-2
Copper source
% Cu (w/w)
3.22
1
2
3
4
Cu(OAc)
Cu(OAc)
CuI
2
2
a
4.02 ± 0.17
9.42 ± 0.18
6.62
a
Amberlyst® A-21
Cu(OAc)
2
a
Average copper content from three different batches of supported catalyst.
The Amberlyst® A-21-based support was prepared from
the commercially available resin, which was first treated with
methanol and dichloromethane before shaking with the
corresponding copper salt in acetonitrile for 16 h (Scheme 1,
Eq (3)). The copper content of each supported catalyst system
was established using inductively coupled plasma atomic
analysis (ICP-MS), and loadings were expressed as a mass
percentage (g of copper per 100 g of support). The results are
summarised in Table 1.
Scheme 1. Preparation of the solid supported copper catalysts.
In an effort to improve the scope and versatility of Cu-
promoted sydnone cycloadditions we decided to investigate
the potential of supported Cu-catalysts for the synthesis of
pyrazoles.
Cycloaddition reactions in batch using supported catalysis
Preliminary cycloaddition studies highlighted that
Amberlyst® A-21 beads were not suitable for this chemistry,
since very low conversion for the cycloaddition reactions was
observed (Table 2, Entries 1-4). This polymer cannot be
employed at temperatures above 100 °C due to its low thermal
resistance. To enhance the performance of A-21-supported
copper(I) iodide, the addition of nitrogen-containing ligands
was considered. The addition of 1 equivalent of N,N,N’,N’-
tetramethylethylenediamine (TMEDA), however, afforded the
Results and discussion
Preparation of supported catalysts
Our initial studies focused on the preparation of supported
catalysts. Two main supports were chosen: Amberlyst® A-21,
which is an amine-based polystyrene resin, and silica gel
modified with additional amine groups to assist copper
coordination. The copper sources chosen to coordinate with
corresponding
Glaser
homocoupled
1,4-diphenyl-1,3-
2
these supports were CuI and Cu(OAc) as they were readily
butadiyne product with no detectable quantities of the desired
pyrazole (Entry 2). On the other hand, the addition of 1
equivalent of 2,2’-bipyridine dramatically changed the
outcome of the reaction since full conversion to the 1,4-
disubstituted pyrazole was achieved in 6 h (Entry 3). Although
this copper-ligand combination led to the formation of product
at 80 °C, further purification of the crude material was
required to separate the bipyridine ligand.
available and represented pre-catalyst complexes at different
oxidation states. The supported catalysts were prepared
1
8,24
following procedures previously reported in the literature.
The two different Cu/silica supports were prepared from
commercial chromatography grade silica gel (30-70 µm particle
size), which was first functionalised to incorporate amino
groups by reaction with the corresponding siloxanes in
refluxing toluene for 24 h (Scheme 1, Eq (1), (2)). After
filtration and drying of the functionalised silica supports, they
were stirred in ethanol in the presence of Cu(OAc) to afford
2
the corresponding catalysts as brightly coloured blue solids.
Table 2. Optimisation of the cycloaddition reaction between N-phenylsydnone and phenylacetylene using supported catalysis.
a
Entry
1
Catalyst (Loading)
A-21·CuI (60 mol%)
A-21·CuI (60 mol%)
A-21·CuI (60 mol%)
Conditions
Result
a)
a)
a)
a)
b)
b)
b)
No reaction
Formation of homocoupled alkyne
100% Conversion
b
2
c
3
4
A-21·Cu(OAc)
2
(40 mol%)
7% Conversion
d
5
Silica-1 (30 mol%)
Silica-2 (30 mol%)
Silica-2 (30 mol%)
100% Conversion in 3 h
6
100% Conversion in 2 h
d
7
100% Conversion in 2 h, > 95% yield after 4 cycles
a
1
b
c
d
Conversions determined by H-NMR spectroscopy. Reaction performed by adding 1 eq. of TMEDA. Reaction performed by adding 1 eq. of 2,2’-bipyridine.
Reaction performed with 1 eq. of the alkyne.
2
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established disproportionation of Cu(I) to inactive Cu(0) and
2
5,26,27
Cu(II).
Indeed, we have observed the formation of
copper mirrors on the glass surface after performing the
reactions in batch using Schlenk tubes under inert
atmosphere (Scheme 2).
The cycloaddition reactions were performed at 140 °C
under inert atmosphere and during variable reaction times (1-
20 h). Using these conditions, a wide scope was developed
employing both aromatic and aliphatic sydnones and diverse
alkynes incorporating different functionalities such as
heteroaromatics, esters and alkyl residues, affording the
corresponding pyrazole products in moderate to excellent
Scheme 2. Proposed mechanism for the copper disproportionation.
For this reason, silica supported alternatives at higher
temperatures were then studied in order to try to find a yields (Scheme 3). In general, aromatic sydnones reacted
system which would afford clean product in one step by faster than N-benzylsydnone, which only generated the
removing the supported catalyst by filtration. Indeed, silica corresponding products when employing phenylacetylene (14
)
supported catalysts performed much better leading to full or ethyl propiolate (15). No pyrazole formation was detected
conversion in 3 h or less (Entries 5-7). Satisfactorily, for both after 24 h with any other alkyne. Also, electron-neutral
Silica-1 and Silica-2 supported catalysts, the amount of alkyne aromatic sydnones (4-8) gave better results than the electron-
required for the cycloaddition to take place could be reduced rich analogues (9-13). As for the alkynes, the ones bearing
to 1 equivalent with no effect on conversion to the pyrazole aromatic and heteroaromatic groups were the ones
product (Entries 5, 7).
Catalyst Silica-2 was the one chosen for further studies gave rather moderate results (
performing best (
4
,
8
,
9
,
13), whereas cyclopentylacetylene
6,
11), presumably due to the
since it provided the product in shorter reaction times (2 h), high volatility of this alkyne, which evaporated during the
the crude products contained lower levels of impurities and reaction.
the same batch of catalyst could be reused up to 4 cycles
without decreasing its performance. Finally, and to our delight,
we noted a dramatic reduction of the loading of copper
promoter required to achieve complete conversion of the
sydnone substrates. Indeed, catalyst loadings of 25-30 mol%
consistently provided optimal performance.
The fact that only one equivalent of alkyne was required,
suggests that the alkyne could not be involved in promoting
the reduction of Cu(II) to Cu(I). Also, no homocoupled diyne,
resulting from Glaser-type processes, was detected in any case
under the present conditions, which is opposite to our
8
previously reported copper-promoted cycloadditions.
Bearing these observations in mind, an alternative
explanation was required to justify the formation of a
copper(I) acetylide as the active reaction intermediate. We
hypothesised, based on literature precedent, that
convergent disproportionation process could be taking place
when employing Cu(OAc) at temperatures above 120 °C.
Based on studies by Mao et al. and as summarised in Scheme
, copper(II) disproportionates to the active catalyst Cu(I)
species together with Cu(III), which may also function as a
a
2
2
2
5
source of Cu(I) after further reduction. The supported Cu(I)
complex can then promote formation of the Cu-acetylide and,
after cycloaddition, the cuprous pyrazole will exchange with
alkyne to allow the catalyst to turnover. We also note the
Scheme 3
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Table 3. Optimisation of a cycloaddition reaction in flow.
Table 4. Evolution of the cycloaddition reaction over time in flow.
1
a
Entry
Residence time / min
Conversion ( H-NMR)
Entry Collection time / h
Collected mass (mg)
Conversion (4:1)
1
2
3
4
2.5
5.0
55%
95%
86%
87%
1
2
3
4
5
6
7
0:00 – 0:30
0:30 – 1:00
1:00 – 1:30
1:30 – 2:00
2:00 – 3:00
3:00 – 4:00
4:00 – 5:00
1.8
5.6
3.7
5.7
7.4
6.0
6.7
67:33
92:8
91:9
92:8
92:8
93:7
95:5
7.5
10.0
Implementation of the cycloadditions in flow
After the successful demonstration of the advantages of
supported catalysts for pyrazole synthesis, the implementation
a
1
Reaction conversion was determined using 400 MHz H NMR spectroscopy.
of the process in flow was attempted. For this purpose, 10 cm Note that φSydnone = 2* φAlkyne, where φ is flow rate.
length stainless steel tubing (1.75 mm inner diameter) was
used to build the cartridges blocking the ends with cotton wool
As Table 4 shows, initially an equilibration time was
to allow confinement of the supported catalyst.
required to ensure complete circulation of both streams along
the flow system and homogeneous mixing, which translated
into an initial lower conversion (Entry 1).
The initial design of the flow reaction consisted of two
syringe pumps, a T-mixer unit for the homogenisation of the
reaction mixture and the positioning of a packed cartridge
inside an oil bath to allow the reaction to reach 140 °C.
However, after this period, excellent conversions were
maintained over a period of 4 hours, affording clean pyrazole
fractions containing minor traces of unreacted sydnone
To optimise the residence time, N-phenylsydnone (0.20 M)
and phenylacetylene (0.10 M) were each dissolved in o-
dichlorobenzene and flowrate adjusted to ensure that mixing
in a 1:1 molar ratio was achieved inside the system. Table 3
summarises the results. For all the cycloadditions performed in
flow, the volume of the cartridge corresponds to the effective
volume after packing the cartridge with the supported catalyst
in each case. Entry 2 highlights that a residence time of 5
minutes was required to give optimal conversion to the
desired pyrazole product. In principle, longer residence times
should give higher conversion but this was not observed in the
current system (Entries 3, 4 vs. Entry 2). The previous set of
experiments was performed in a 48-hour period using the
same prepacked cartridge (Entry 2 performed on day 1, Entries
(Entries 2-6). Interestingly, after 4 h, conversion to product
was still very high but the crude product contained higher
levels of impurities (Entry 7). We therefore decided to perform
the cycloadditions over a period of 4-5 hours confident that
this would provide high yields of pyrazole products of high
purity.
1, 3 and 4 performed on day 2). These results suggest that the
catalyst loses its efficiency over time, and so for this reason,
we decided to prepare fresh cartridges for the optimisation
study in order to ensure that the results were comparable.
Another parameter we considered for the optimisation was
the solvent. Satisfactorily, 100% conversion was achieved after
5
minutes when performing the model reaction using toluene
instead of o-dichlorobenzene in the presence of a back
pressure regulator (BPR) in order to raise the pressure and
keep the solvent in the liquid state.
Once the optimal reaction conditions were found, we
decided to study the efficiency of the catalyst over time. To do
so, the model reaction was run over a period of 5 h collecting
and analysing aliquots at different time points (Table 4).
Scheme 4. Scope for the cycloaddition reaction under flow conditions.
4
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can be reused and are thermally resistant to the required
reaction conditions. In the present case, a 2 mL empty HPLC
column (Knauer, A2103-1) with 7 µm frits was chosen. To
complete the system, an HPLC pump and a back-pressure
regulator were also employed, and the system was further
simplified by using only one feed containing both the sydnone
and the alkyne (no reaction between them occurs at room
temperature).
When applying the previous set of conditions (140 °C,
R
PhMe, t = 5 min) on both aromatic sydnones and ethyl
propiolate, successful results were obtained (Scheme 5). Even
though this set of conditions was not optimal for this new flow
system, since full conversion was not reached after 5 minutes,
between 50-100 mg of pyrazole products could be produced
with this larger scale setup.
Scheme 5. Initial tests for the scale-up of the cycloaddition reactions in flow.
Having found optimal parameters to perform these
cycloaddition reactions, the expansion of the scope was next
2
8
Experimental
pursued employing the flow platform (Scheme 4).
Depending on the nature of the substrate, residence times
from 5 minutes to 15 minutes were employed for the synthesis
of the substrates already prepared by means of supported
catalysis in batch.
General procedure for the synthesis of 1,4-disubstituted pyrazoles
in batch.
To a stirred solution of sydnone (1 eq.) and supported catalyst
Silica-2 (0.3 eq., 4.02% Cu) in o-dichlorobenzene (0.20 - 0.25
Best results were obtained with phenylacetylene and ethyl
propiolate, similarly to the batch procedure. When 2-
ethynylpyridine, cyclopentylacetylene or propargyl alcohol
were employed, the reaction rates were slower so that higher
residence times were needed to increase conversion in most
cases (tR = 10, 15 min). Interestingly, when using 2-
M) under N
eq.). After stirring at room temperature for 5 minutes, the
mixture was heated at 140 C for the designated time. After
2
at room temperature, was added the alkyne (1
°
cooling, the reaction mixture was filtered and the crude
product was purified by flash chromatography on silica gel
(
eluting solvent: 5% ethyl acetate in heptane, unless otherwise
stated). Further purification of the pyrazole products could be
realised by recrystallisation from CH Cl – heptane if required.
ethynylpyridine (8, 13), moderate yields were obtained
compared to the batch examples, which could be attributed to
potential coordination of pyridine to the copper centres of the
catalyst along the cartridge, preventing full pyrazole recovery
after the reaction. Also, the low yields obtained under these
conditions for the alcohol-containing pyrazoles suggest
potential degradation of the products inside the microreactor.
For example, as these reactions require heating at high
temperatures over prolonged periods of time, it is conceivable
that trans-esterification with the silica support results in some
2
2
General procedure for the synthesis of 1,4-disubstituted pyrazoles
in flow.
Two feed solutions were employed: stream A containing the
sydnone of choice in toluene (0.025 M), and stream B
containing the alkyne in toluene (0.050 M), both driven by
A B
syringe pumps (φ = 2·φ ). These were mixed in a PEEK T-mixer
connection (P-713, IDEX) before entering the microreactor,
consisting of a 10 cm stainless steel cartridge packed with the
supported copper catalyst, at 140 °C for 5 to 15 minutes. By
removing the solvent in vacuo, the desired pyrazole products
were obtained. In some cases, further purification was
achieved by flash chromatography on silica gel (5-10% ethyl
acetate in heptane) and/or by recrystallisation from
dichloromethane/heptane.
losses of the pyrazole
7, as this compound was recovered
cleanly but in low amounts, and no starting material was
2
recovered.
9
Scaling-up of the flow process
The currently developed flow system employing supported
catalysis allowed the preparation of a range of 1,4-
disusbtituted pyrazoles in a regioselective manner in relatively
short reaction times. Although this provides proof of concept
for the implementation of this technology, the absolute
amount of pyrazole products generated with the setup is quite
low due to the small internal volume of the cartridge. To show
that these reactions can be run equally well at larger scale, we
developed a system that allowed scaling up of the process to
generate practically useful amounts of these products over a
few hours.
Conclusions
We have developed new methodology for the regioselective
synthesis of 1,4-disubstituted pyrazoles via cycloaddition
reactions between sydnones and alkynes employing a silica-
supported copper catalyst. This methodology has also been
implemented in flow for the first time, which led to
significantly reduced reaction times, and proved the feasibility
of the continuous process. Moreover, scaling-up of this flow
process has successfully been achieved for the synthesis of
For this purpose, we considered that a suitable alternative
to stainless steel tubing would be to employ empty stainless
steel HPLC columns, since they are easy to fill with catalyst,
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ester-containing pyrazole derivatives in practical amounts 25.
showing the potential that this technology can offer towards
Z. Mao, Z. Wang, Z. Xu, F. Huang, Z. Yu and R. Wang, Org.
Lett., 2012, 14, 3854-3857.
A. E. King, T. C. Brunold and S. S. Stahl, J. Am. Chem. Soc.,
2
6.
the development of other solid-supported catalysed processes.
2
009, 131, 5044-5045.
2
7.
A. E. King, L. M. Huffman, A. Casitas, M. Costas, X. Ribas
and S. S. Stahl, J. Am. Chem. Soc., 2010, 132, 12068-
Acknowledgements
1
2073.
This work was supported by the FP7 Marie Curie Actions of the 28
European Commission via the ITN ECHONET Network (MCITN-
ICP-MS analysis of pyrazoles5 and 9 (x2) highlighted only
small quantities of leaching (<400 ppm) under conditions
highlighted in Scheme 4 over a 2 hour period.
2012-316379).
2
9
We are grateful to a reviewer for this suggestion.
Notes and references
1
.
E. Arbaciauskiené, G. Vilkauskaité, G. A. Eller, W. Holzer
and A. Sackus, Tetrahedron, 2009, 65, 7817-7824.
S. Ishibuchi, H. Morimoto, T. Oe, T. Ikebe, H. Inoue, A.
Fukunari, M. Kamezawa, I. Yamada and Y. Naka, Bioorg.
Med. Chem. Lett., 2001, 11, 879-882.
2.
3
4
.
.
C. Lamberth, Heterocycles, 2007, 71, 1467-1502.
S. Fustero, M. Sánchez-Roselló, P. Barrio and A. Simón-
Fuentes, Chem. Rev., 2011, 111, 6984-7034.
5
6
7
8
9
1
.
D. L. Browne, M. D. Helm, A. Plant and J. P. A. Harrity,
Angew. Chem. Int. Ed., 2007, 46, 8656-8658.
.
D. L. Browne, J. F. Vivat, A. Plant, E. Gomez-Bengoa and J.
P. A. Harrity, J. Am. Chem. Soc., 2009, 131, 7762-7769.
R. S. Foster, J. Huang, J. F. Vivat, D. L. Browne and J. P. A.
Harrity, Org. Biomol. Chem., 2009, 7, 4052-4056.
J. Comas-Barceló, R. S. Foster, B. Fiser, E. Gomez-Bengoa
and J. P. A. Harrity, Chem. Eur. J., 2015, 21, 3257-3263.
R. S. Foster, H. Jakobi and J. P. A. Harrity, Tetrahedron
Lett., 2011, 52, 1506-1508.
.
.
.
0.
S. Kolodych, E. Rasolofonjatovo, M. Chaumontet, M.-C.
Nevers, C. Créminon and F. Taran, Angew. Chem. Int. Ed.,
2013, 52, 12056-12060.
1
1.
2.
S. Specklin, E. Decuypere, L. Plougastel, S. Aliani and F.
Taran, J. Org. Chem., 2014, 79, 7772-7777.
E. Decuypere, S. Specklin, S. Gabillet, D. Audisio, H. Liu, L.
Plougastel, S. Kolodych and F. Taran, Org. Lett., 2015, 17,
1
362-365.
13.
C. Theunissen, M. Lecomte, K. Jouvin, A. Laouiti, C.
Guissart, J. Heimburger, E. Loire and G. Evano, Synthesis,
2014, 1157-1166.
1
1
4.
5.
J. F. Normant, Synthesis, 1972, 63-80.
D. L. Browne, B. J. Deadman, R. Ashe, I. R. Baxendale and
S. V. Ley, Org. Process Res. Dev., 2011, 15, 693-697.
M. Fuchs, W. Goessler, C. Pilger and C. O. Kappe, Adv.
Synth. Catal., 2010, 352, 323-328.
I. R. Baxendale, S. V. Ley, A. C. Mansfield and C. D. Smith,
Angew. Chem. Int. Ed., 2009, 48, 4017-4021.
1
6.
7.
1
18.
19.
20.
21.
T. Miao and L. Wang, Tetrahedron Lett., 2007, 48, 95-99.
Q. Wu and L. Wang, Synthesis, 2008, 2007-2012.
T. Miao and L. Wang, Synthesis, 2008, 363-368.
S. M. Opalka, J. K. Park, A. R. Longstreet and D. T.
McQuade, Org. Lett., 2013, 15, 996-999.
22.
23.
24.
J. Bao and G. K. Tranmer, Chem. Commun., 2015, 51,
3
037-3044.
A. R. Bogdan and N. W. Sach, Adv. Synth. Catal., 2009,
51, 849-854.
3
C. Girard, E. Önen, M. Aufort, S. Beauvière, E. Samson and
J. Herscovici, Org. Lett., 2006, 8, 1689-1692.
6
| J. Name., 2012, 00, 1-3
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Catalysis Science & Technology
View Article Online
DOI: 10.1039/C5CY02247A
Graphical Abstract
Go with the flow.
Copper(II) salts promote the regioselective synthesis of 1,4-disubstituted pyrazoles via the
formation of reactive Cu(I) acetylide species. By using supported copper catalysts we have
been able to enhance this methodology, significantly reducing the copper loadings to 30 mol%
and, in addition, the amount of alkyne required. Implementation under continuous flow
dramatically affected reaction times, going from 16 h to residence times of only 5 to 15 min. In
addition, with this technology, the reaction can be performed in toluene and can be easily
scaled up.