Continuous-flow synthesis of 3,5-disubstituted pyrazoles: Via sequential alkyne homocoupling and Cope-type hydroamination

Article abstract of DOI:10.1039/c9ra01590f

A flow chemistry-based approach is presented for the synthesis of 3,5-disubstituted pyrazoles via sequential copper-mediated alkyne homocoupling and Cope-type hydroamination of the intermediary 1,3-diynes in the presence of hydrazine as nucleophilic reaction partner. The proposed multistep methodology offers an easy and direct access to valuable pyrazoles from cheap and readily available starting materials and without the need for the isolation of any intermediates.

Full text of DOI:10.1039/c9ra01590f

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Continuous-flow synthesis of 3,5-disubstituted
pyrazoles via sequential alkyne homocoupling and
Cope-type hydroamination†
Cite this: RSC Adv., 2019, 9, 8197
abc
ab
A´dam Georgiades,a Daniel Ozsvara and Ferenc Fulop
*
*
Sandor B. O¨ tvos,
´
¨
´
´
´
´
¨ ¨
A flow chemistry-based approach is presented for the synthesis of 3,5-disubstituted pyrazoles via sequential
copper-mediated alkyne homocoupling and Cope-type hydroamination of the intermediary 1,3-diynes in
the presence of hydrazine as nucleophilic reaction partner. The proposed multistep methodology offers
an easy and direct access to valuable pyrazoles from cheap and readily available starting materials and
without the need for the isolation of any intermediates.
Received 3rd March 2019
Accepted 4th March 2019
DOI: 10.1039/c9ra01590f
rsc.li/rsc-advances
However, they typically involve numerous drawbacks, such as
harsh reaction conditions, selectivity issues, and the necessity
Introduction
of environmentally unfriendly reactants and/or special starting
materials.6 In the past few years, a wide array of modern
synthetic methods have been reported to overcome the above
difficulties and to efficiently obtain pyrazoles with diverse
substitution patterns.7 For example, intermolecular Cope-type
hydroamination of 1,3-diynes with hydrazine was recently
shown as a powerful strategy for the synthesis of 3,5-disubsti-
tuted pyrazoles.8 The reaction occurs via nucleophilic attack of
hydrazine onto the diyne core and results in an allene inter-
mediate, which undergoes electrophilic cyclization to yield
a new C–N bond leading to the desired pyrazole motif (Scheme
2).9 The transformation requires no catalyst and proceeds
smoothly without any additives (such as strong bases or acids)
Nitrogen-containing heterocycles have well-known and indis-
putable importance in synthetic and pharmaceutical chemistry.
Among their ve-membered counterparts, pyrazoles are of
outstanding importance with impressively diversied applica-
tions.1 As a core structure, the pyrazole motif constitutes
a myriad of pharmaceutically interesting compounds with
a
wide spectrum of biological activities, such as anti-
hiperglycemic, analgesic, anti-inammatory, antidepressant,
antipyretic, antibacterial, antiviral, antituberculotic and
sedative-hypnotic effects (Scheme 1).2 Besides their biological
importance, pyrazoles are versatile building blocks in organic
chemistry, and they are frequently used as ligands and
chelating agents in coordination chemistry and catalysis.3
Furthermore, pyrazoles and their derivatives are widely
employed in the agrochemical industry as insecticides, fungi-
cides, and herbicides.4
Because of the outstanding importance of pyrazoles, their
syntheses have attracted much attention. The most typical
methods for the preparation of substituted pyrazoles involve (i)
cyclocondensation of 1,3-dicarbonyls or a,b-unsaturated
carbonyls with hydrazine derivatives and (ii) [3 + 2] cycloaddi-
tion of alkynes or olens with 1,3-dipoles such as nitrile imines,
diazoalkanes, and sydnones.1b,5 Even multisubstituted pyr-
azoles can be achieved by using the aforementioned methods.
aInstitute of Pharmaceutical Chemistry, University of Szeged, Interdisciplinary
¨
¨
Excellence Center, Eotvos u. 6, H-6720 Szeged, Hungary. E-mail: otvossandor@
pharm.u-szeged.hu; fulop@pharm.u-szeged.hu; Fax: +36-62-545-705; Tel: +36-62-
545-768; +36-62-545-562
b
¨
¨
MTA-SZTE Stereochemistry Research Group, Hungarian Academy of Sciences, Eotvos
u. 6, H-6720 Szeged, Hungary
cInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, A-8010
Graz, Austria
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra01590f
Scheme 1 Examples for pharmacologically important pyrazoles.
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Optimization of the 1,3-diyne synthesis
The catalytic dimerization of 4-ethynyltoluene was chosen as
a model reaction for the investigation of diyne synthesis
(Scheme 3). As concerns the source of the catalytic metal, there
are numerous examples for the use of heterogeneous copper
catalysts in acetylenic homocouplings. Indeed, these materials
exhibit various benets including reusability and the ease of
product isolation.16 However, for the development of a multi-
step method we preferred soluble copper sources over solid
catalysts in order to avoid uncontrollable leaching issues and to
create a robust synthesis system.
In copper-mediated oxidative homocouplings of acetylenes,
copper ions of +1 and +2 oxidation states are known to operate
cooperatively as active species.17 Therefore, various Cu(II) and Cu(I)
salts and complexes were considered as sources for the catalytic
metal (Table S1†). Since only homogeneous solutions can be
applied in the reaction channels, thorough solubility tests were
carried out by using not only the starting alkyne and the copper
catalyst but also hydrazine monohydrate, in order to avoid precip-
itation in both reaction steps. Tests were carried out with DMSO,
EtOAc, MeCN, acetone and EtOH as possible solvents. DMSO and
EtOH proved to be compatible with the alkyne component,
hydrazine and also with [Cu(phen)(PPh3)2]NO3 or CuBr2 as catalyst.
Consequently, they were selected as possible solvents for the reac-
tions (see Table S1† for the detailed solubility tests).
Scheme 2 Plausible mechanism of the reaction between 1,3-diyne
and hydrazine.9
under reasonably mild conditions. As concerns the components
of the Cope-type hydroamination, hydrazine and its derivatives
are readily available, while the 1,3-diyne starting material can be
accessed by catalytic oxidative dimerization of terminal acety-
lenes, which is typically performed by means of copper catal-
ysis. The latter process utilizes either soluble or heterogeneous
catalyst sources in the presence of various bases and ligands.10
Flow chemistry offers numerous benets for chemical
syntheses,11 including multistep processes,12 but there are only
a few instances in which these gains have been exploited for the
synthesis of substituted pyrazoles and their derivatives.13 On the
basis of the above ndings, we envisioned that continuous-ow
chemistry may be an ideal platform for a telescoped reaction
sequence of catalytic alkyne homocoupling and the Cope-type
hydroamination of the resulting 1,3-diynes to yield valuable
3,5-disubstituted pyrazoles directly from terminal acetylenes as
cheap and readily available starting materials. The proposed
integrated synthesis method would permit a facile access to
target pyrazoles without the isolation of any intermediates and
with signicantly less purication issues. Moreover, both
alkyne dimerization and the Cope-type hydroamination require
long reaction times,8,10 and thus the complete batch synthesis is
a rather lengthy process. We, therefore, also aimed to utilize the
technological benets of ow chemistry to achieve chemical
intensication as compared with earlier batch processes.14
Thus, we are reporting our results on the continuous-ow
synthesis of 3,5-disubstituted pyrazoles via sequential alkyne
homocoupling and Cope-type hydroamination.
The dimerization of 4-ethynyltoluene was next examined
with the selected copper sources in a 14 mL stainless steel
reaction coil (internal diameter: 0.76 mm, length: 30.5 m) under
the following initial conditions: 120 C and 0.2 mL minꢁ1 ow
ꢀ
rate (70 min residence time, Scheme 3). The alkyne was applied
in a concentration of 0.075 M (higher concentrations occa-
sionally led to precipitation) in combination with 0.06 equiv. of
the copper catalyst in DMSO or EtOH as solvent. With
[Cu(phen)(PPh3)2]NO3 as catalyst no conversion was detected
either in DMSO or in EtOH even in the presence of 0.5 equiv. of
N,N-diisopropylethylamine (DIEA) as a base (Table 1, entries 1–
4). In contrast, CuBr2 in combination with N,N,N0,N0-tetrame-
thylethylenediamine (TMEDA) as ligand and DIEA as base (0.5
equiv. each) proved to be superior and offered quantitative
conversion and selective diyne formation in DMSO as solvent
(Table 1, entry 5). On investigation of the effects of the
auxiliaries, it was found that the amount of TMEDA and DIEA
can be reduced to 0.25 equiv. without loss in conversion (Table
1, entries 6 and 7). It was also observed that the joint application
of the ligand and the base is necessary: conversion was reduced
signicantly when using only TMEDA or DIEA as the sole
additive (Table 1, entries 8 and 9). In the absence of the ligand
and base, precipitation and clogging occurred in the reactor
Results and discussion
The planned synthesis consists of (i) a metal-catalyzed coupling
step and (ii) the subsequent non-catalytic hydroamination with
hydrazine involving an electrophilic cyclization to yield the
pyrazole motif. In the second step, traces of the catalytic metal
from the homocoupling may open up unwanted reaction
pathways and involve the formation of by-products.15 Therefore,
instead of a one-step/one-pot method, a two-step telescoped
process seems more feasible with in-line metal removal aer
the rst step. In the rst stage of the research, a step-by-step
reaction optimization was projected, and aer being familiar
with both reactions, separate steps were next arranged into
a multistep telescoped ow sequence where the intermediary
1,3-diyne is transformed immediately without the need for
isolation.
Scheme 3 Oxidative homocoupling of 4-ethynyltoluene in a contin-
uous-flow reactor.
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Table 1 Optimization of the homocoupling of 4-ethynyltoluene in a 14 mL coil reactor. Fixed conditions: 1 equiv. alkyne (c ¼ 0.075 M), 6 mol%
catalyst, 120 ꢀC
Additives (equiv.)
Entry
Catalyst
TMEDA
DIEA
Solvent
Flow ratea (mL minꢁ1
)
Conv.b (%)
1
2
3
4
5
6
7
8
[Cu(phen)(PPh3)2]NO3
[Cu(phen)(PPh3)2]NO3
[Cu(phen)(PPh3)2]NO3
[Cu(phen)(PPh3)2]NO3
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
0
0
0
0
0.5
0.25
0.1
0.25
0
0
0
DMSO
EtOH
DMSO
EtOH
0.2 (70)
0.2 (70)
0.2 (70)
0.2 (70)
0.2 (70)
0.2 (70)
0.2 (70)
0.2 (70)
0.2 (70)
0.2 (70)
0.5 (28)
1 (14)
0
0
0
0
0.5
0.5
0.5
0.25
0.1
0
0.25
0
0.5
0.5
0.5
0.5
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
100c
100c
30c
20c
16c
N.d.d
100c
100c
65c
54c
9
10
11
12
13
14
0
0.5
0.5
0.5
0.5
1.5 (10.4)
2 (7)
CuBr2
a
Residence time (in min units) is shown in parentheses. b Determined by 1H NMR spectroscopy of the crude material. c Chemoselectivity of diyne
formation was 100%. d No data, clogging occurred.
tubing (Table 1, entry 10). To our delight, residence time could a satisfying conversion of 89% was measured with exclusive
successfully be reduced from 70 min to 28 and even to 14 min pyrazole formation. Lower ow rates were not investigated so
(0.5 and 1 mL minꢁ1 ow rate, respectively) without any that the residence times of the individual reaction steps remain
decrease in the quantitative conversion (Table 1, entries 11–14). compatible in the telescoped system.
Optimization of the Cope-type hydroamination
Telescoped pyrazole synthesis
Aer having established the best conditions for 1,3-diyne
synthesis, the Cope-type hydroamination was studied utilizing
preformed 1,4-di-p-tolylbuta-1,3-diyne as model substrate. A
0.0375 M DMSO solution of the diyne (half of the concentration
of the starting alkyne employed in the rst coupling step) was
combined in a T-piece with a hydrazine stream (60 wt% aqueous
solution containing 0.1125 M hydrazine in DMSO) and was
passed through a 14 mL reaction coil (internal diameter: 0.76
mm, length: 30.5 m) at 120 ꢀC utilizing various ow rates
(Scheme 4). The need for the relatively large excess of hydrazine
is explained by the fact that it not only plays a role as a reaction
partner in the actual hydroamination, but it also participates in
the nal proton transfer leading to the pyrazole product
(Scheme 2).9
Aer getting familiar with the optimum conditions of both the
copper-catalyzed alkyne dimerization and the Cope-type
hydroamination/cyclization, next individual reaction steps
were combined (Scheme 5). To be able to synchronize the
residence times in the reactor components, a 3.5 mL heated coil
was used for the alkyne homocoupling reaction. The solution of
4-ethynyltoluene (0.075 M) was pumped continuously at 0.1
mL minꢁ1 ow rate which gave a residence time of 35 min. A
subsequent column packed with a thiourea-based scavenger
The thermal transformation was found to be rather sensitive
to residence times applied. When both pumps were operated at
a ow rate of 0.5 mL minꢁ1 (14 min residence time), a conver-
sion of merely 10% occurred (Fig. 1). Upon increasing the
residence time to 70 min (both pumps at 0.1 mL minꢁ1),
Fig. 1 Investigation of the effects of residence time on the hydro-
amination of 1,4-di-p-tolylbuta-1,3-diyne with hydrazine. Conditions:
1 equiv. diyne (c ¼ 0.0375 M), 3 equiv. hydrazine (c ¼ 0.1125 M), DMSO
Scheme 4 Continuous-flow reactor set-up for the hydroamination of as solvent, 120 ꢀC, pumps operated at the same flow rate (see Scheme
1,4-di-p-tolylbuta-1,3-diyne.
4). (Chemoselectivity of pyrazole formation was 100% in all reactions).
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Scheme 5 Schematic representation of the two-step continuous-flow pyrazole synthesis.
resin was installed to remove copper species aer the homo- yields were in the range of 84–90% aer chromatographic
coupling took place. The resulting diyne solution was next purication. It should be noted that aliphatic alkynes such as 3-
combined with a hydrazine stream (60 wt% aqueous solution cyclohexyl-1-propyne and oct-1-yne constitute a limitation yet.
containing 0.1125 M hydrazine in DMSO) at 0.1 mL minꢁ1
.
In these cases, diyne formation was not complete possibly
Pyrazole formation took place during passage through a 14 mL because of the lack of conjugation, and, in addition, conversion
heated coil at a cumulative ow of 0.2 mL minꢁ1, which corre- in hydroamination/cyclization was also low resulting in non-
sponded to a residence time of 70 min.
acceptable yields.
ꢀ
When both coils were heated at 120 C similarly to step-by-
In the case of 3-ethynylthiophene, a scale-up experiment was
step optimizations, all akyne starting material got consumed carried out by simply prolonging the operation time without any
and the corresponding pyrazole was formed to an extent of 76% change in the optimized conditions. We were delighted to nd
(together with 24% of 1,4-di-p-tolylbuta-1,3-diyne; Table 2, entry that the ow system was stable for an extended period of 16 h
1). To improve pyrazole formation, the hydroamination coil was giving 0.52 g of pure 3-(thiophen-3-yl)-5-(thiophen-3-ylmethyl)-
replaced with a 17.5 mL one affording a residence time of
87.5 min at a ow rate of 0.2 mL minꢁ1. The increased residence
time improved pyrazole formation to 86% at 120 ꢀC; and, nally,
Table 3 Exploring the reactivity of different alkynes in the telescoped
ꢀ
increasing the temperature to 140 C resulted in 98% pyrazole
formation without traces of unreacted alkyne in the crude
material (Table 2, entries 2 and 3).
alkyne homocoupling–hydroamination/cyclization process. Condi-
tions for homocoupling: 1 equiv. alkyne (c ¼ 0.075 M), 6 mol% CuBr2 as
catalyst, DMSO as solvent, 120 ꢀC, 0.1 mL minꢁ1 flow rate, 35 min
residence time. Conditions for hydroamination: 3 equiv. ꢁo1f hydrazine
(c ¼ 0.1125 M), DMSO as solvent, 140 ꢀC, 0.1 mL min flow rate,
87.5 min residence time
With optimized conditions for the telescoped pyrazole
synthesis in hand, the reactivity of different alkynes was next
investigated. Excellent results were achieved with phenyl-
acetylene, its methyl-substituted derivatives, and with 3-ethy-
nylthiophene (Table 3). The starting alkynes were quantitatively
converted to the corresponding diynes (no traces of unreacted
alkyne were found in the crude material), and aer the subse-
quent hydroamination/cyclization the corresponding pyrazoles
were obtained with yields of 90–98%. The reactions were che-
moselective, no sideproduct formation was detected, isolated
Entry
Alkyne
Product
Yielda (%)
1
98 (90)b
2
3
90 (84)b
Table 2 Optimization of the hydroamination step of the consecutive
process. Conditions for homocoupling: 1 equiv. 4-ethynyltoluene (c ¼
0.075 M), 6 mol% CuBr2 as catalyst, DMSO as solvent, 120 ꢀC, 35 min
residence time. Conditions for hydroamination: 3 equiv. hydrazine (c ¼
0.1125 M), DMSO as solvent
96 (84)b
94 (85)b
Temperature
(ꢀC)
Residence time
(min)
Entry
Yielda (%)
4
1
2
3
120
120
140
70
87.5
87.5
76
86
98
a
NMR yield, determined by 1H NMR spectroscopy of the crude material.
a
NMR yield, determined by 1H NMR spectroscopy of the crude material. No traces of unreacted alkyne were found in the crude material.
b
No traces of unreacted alkyne were found in the crude material.
Isolated yields indicated in parentheses.
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1H-pyrazole corresponding to an isolated yield of 81%. As DIEA (0.19 mmol, 0.25 equiv.) in 10 mL DMSO. The solution was
a result of the in-line copper scavenging, the crude product carefully homogenized and pumped through a 14 mL coil
obtained in the scale-up experiment contained only a negligible reactor (internal diameter: 0.76 mm, length: 30.5 m) under the
copper amount of 0.3 ppm as determined by ICP-MS.
selected conditions.
Optimization of the Cope-type hydroamination. 1,4-Di-p-
tolylbuta-1,3-diyne (0.375 mmol, 1 equiv.) and hydrazine
(1.125 mmol, 3 equiv., 60 wt% aqueous solution used) were
dissolved separately in 10 mL DMSO each. The solutions were
pumped as separate streams by using two HPLC pumps. Aer
being combined in a T-piece, the resulting mixture was passed
through a 14 mL reaction coil (internal diameter: 0.76 mm,
length: 30.5 m) under the selected conditions.
Procedure for the telescoped pyrazole synthesis. The
appropriate alkyne (0.75 mmol, 1 equiv.) was added to a mixture
of CuBr2 (0.045 mmol, 6 mol%), TMEDA (0.19 mmol, 0.25
equiv.), and DIEA (0.19 mmol, 0.25 equiv.) in 10 mL DMSO. The
reaction mixture was homogenized and pumped through
a 3.5 mL reaction coil (internal diameter: 0.76 mm, length: 7.5
m) under the selected conditions. The resulting stream was
passed through a stainless steel column (internal dimensions:
4.6 ꢂ 150 mm) charged with 0.9 g QuadraPure® TU. Aer
leaving the scavenger column, the mixture was combined with
a stream of hydrazine solution (60 wt% aqueous solution con-
taining 0.1125 M hydrazine in DMSO) and was passed through
a 17.5 mL reaction coil (internal diameter: 0.76 mm, length:
38.5 m) under the selected conditions.
Conclusion
A two-step continuous-ow methodology has been developed
for the synthesis of 3,5-disubsituted pyrazole derivatives from
terminal alkynes and hydrazine monohydrate as readily avail-
able starting materials. The process relied on (i) the copper-
mediated homocoupling of the alkyne component in the pres-
ence of CuBr2 as a simple soluble catalyst source, and (ii) the
subsequent Cope-type hydroamination of the in situ formed 1,3-
diyne with hydrazine as nucleophilic reaction partner. Aer an
initial step-by-step optimization procedure, individual reaction
components were organized into an uninterrupted ow
sequence where, aer in-line copper removal, the intermediary
diyne was transformed further aer being combined with
a hydrazine stream. The developed process proved to be appli-
cable for a range of aromatic alkynes and permitted a simple
and easy access to a diverse set of pyrazoles without the isola-
tion of any intermediates. With a cumulative residence time of
around 2 h, the ow methodology involved a signicant
chemical intensication as compared with the corresponding
batch reaction.
Aer each reaction, 20 mL water or, in the case of homo-
couplings, 20 mL 0.1 M aqueous ethylenediaminetetraacetic
acid (EDTA) solution was added to the collected mixtures and
the aqueous phase was extracted with 3 ꢂ 30 mL of EtOAc. The
combined organic phases were washed with brine (2 ꢂ 10 mL),
dried over Na2SO4, and concentrated in vacuo. Column chro-
matography purication was carried out with mixtures of n-
hexane/EtOAc as eluent. Between two ow experiments, the
reactor was washed with DMSO–MeOH–DMSO, respectively,
Experimental section
General information
Reagents and materials were commercially available and were
used as received. Analytical thin-layer chromatography was
performed on Merck silica gel 60 F254 plates and ash column
chromatography on Merck silica gel 60. Compounds were
visualized by means of UV or KMnO4. H NMR and 13C NMR
1
10 min each at ow rates of 1 mL minꢁ1
.
spectra were recorded on a Bruker Avance DRX 400 spectrom-
eter, in CDCl3 as solvent, with TMS as internal standard, at
400.1 and 100.6 MHz, respectively. Copper concentration was
determined by inductively coupled plasma mass spectrometry
(ICP-MS), using an Agilent 7700x-type instrument equipped
with a collision cell aer digestion with concentrated HNO3.
The determination was carried out on the isotope 63Cu, with He
as the collision gas.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
General procedure for the ow reactions
Reactions were carried out in a home-made ow reactor con- We are grateful to the Hungarian Research Foundation
sisting of HPLC pumps (JASCO PU-880 and Knauer AZURA P 2.1 (OTKA No. K 115731). The nancial support of the GINOP-
S), stainless steel coils (internal diameter: 0.76 mm, length: 7.5, 2.3.2-15-2016-00014 project are acknowledged. Ministry of
30.5 or 38.5 m), and a commercially available 50 bar back- Human
pressure regulator (IDEX P-455 BPR Assembly 750, PEEK). The FEKUSTRAT is acknowledged. SBO acknowledges the
parts of the system were connected with stainless steel and Premium Post Doctorate Research Program of the Hungarian
Capacities,
Hungary
grant
¨
20391-3/2018/
´
PEEK capillary tubing (254 mm internal diameter). The reaction Academy of Sciences. AG was supported by the UNKP-17-3
coils were immersed in a heated oil bath. New National Excellence Program of the Ministry of
Optimization of 1,3-diyne synthesis. 4-Ethynyltoluene Human Capacities. Financial supports are highly appreci-
´
´
´
(0.75 mmol, 1 equiv.) was added to a mixture of CuBr2 ated. We are grateful to Prof. Arpad Molnar for proofreading
(0.045 mmol, 6 mol%), TMEDA (0.19 mmol, 0.25 equiv.), and our manuscript.
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