Microwave-assisted and continuous flow multistep synthesis of 4-(pyrazol-1-yl)carboxanilides

Article abstract of DOI:10.1021/jo2009824

A series of 4-(pyrazol-1-yl)carboxanilides active as inhibitors of canonical transient receptor potential channels were synthesized in an efficient three-step protocol using controlled microwave heating. The general synthetic strategy involves condensation of 4-nitrophenylhydrazine with appropriate 1,3-dicarbonyl building blocks, followed by reduction of the nitro group to the amine, which is then amidated with carboxylic acids. Compared to the conventional protocol a dramatic reduction in overall processing time from ～2 days to a few minutes was achieved, accompanied by significantly improved product yields. In addition, the first two steps in the synthetic pathway were also performed under continuous flow conditions providing similar isolated product yields. As an alternative to the three-step protocol, a novel two-step route to the desired 4-(pyrazol-1-yl)carboxanilides was devised involving condensation of 4-bromophenylhydrazine with appropriate 1,3-dicarbonyl building blocks, followed by Pd-catalyzed Buchwald-Hartwig amidation with carboxylic acid amides.

Full text of DOI:10.1021/jo2009824

ARTICLE
pubs.acs.org/joc
Microwave-Assisted and Continuous Flow Multistep Synthesis of
4-(Pyrazol-1-yl)carboxanilides
David Obermayer, Toma N. Glasnov,* and C. Oliver Kappe*
Christian Doppler Laboratory for Microwave Chemistry (CDLMC) and Institute of Chemistry, Karl-Franzens-University Graz,
Heinrichstrasse 28, A-8010 Graz, Austria
S Supporting Information
b
ABSTRACT: A series of 4-(pyrazol-1-yl)carboxanilides active
as inhibitors of canonical transient receptor potential channels
were synthesized in an efficient three-step protocol using
controlled microwave heating. The general synthetic strategy
involves condensation of 4-nitrophenylhydrazine with appro-
priate 1,3-dicarbonyl building blocks, followed by reduction of
the nitro group to the amine, which is then amidated with
carboxylic acids. Compared to the conventional protocol a dramatic reduction in overall processing time from ∼2 days to a few
minutes was achieved, accompanied by significantly improved product yields. In addition, the first two steps in the synthetic pathway
were also performed under continuous flow conditions providing similar isolated product yields. As an alternative to the three-step
protocol, a novel two-step route to the desired 4-(pyrazol-1-yl)carboxanilides was devised involving condensation of 4-bromo-
phenylhydrazine with appropriate 1,3-dicarbonyl building blocks, followed by Pd-catalyzed BuchwaldꢀHartwig amidation with
carboxylic acid amides.
’ INTRODUCTION
The pyrazole ring is an important heterocyclic core structure
in a large number of biologically active compounds. The spec-
trum of pharmaceutical action of pyrazole derivatives encom-
passes, for example, substances acting on the central nervous
system, pharmacodynamic agents, drugs aimed at metabolic
diseases, and chemotherapeutics.1 Recent examples are the
CB1 cannabinoid receptor antagonist Rimonabant (Sanofi-
Aventis)2 and analogous molecules active as protein kinase
Figure 1. Pyrazole-based family of TRPC inhibitors/NFAT transcrip-
tion factor regulators.6ꢀ10
inhibitors, in addition to anti-estrogens acting as potential
antitumor therapeutics.3 The past decade brought the discovery
Abbott,8 Astellas,9 and Boehringer-Ingelheim10 into the devel-
of a new class of drugs targeting the Na+/Ca2+ signaling path-
opment of discovery libraries in the search for potential lead
ways, which play a key role in many pathogenic processes
compounds in these areas.7
Today, performing organic synthesis under continuous flow
including systemic diseases, inflammation, and cancer.1,4 One
important topic in this rapidly growing field are drugs which are
conditions is getting widely accepted in both industry and
tuning the activity of canonical transient receptor potential
channels (TRPC), controlling the influx of intracellular Ca2+
academia, while at the same time the available technology is
getting more mature.11,12 One of the important features of flow
into a plethora of mammalian cell types.5 Mori and co-workers
reactors is the ability of the used capillaries or channels (∼50ꢀ
recently described a number of 4-(pyrazol-1-yl)carboxanilides
(Figure 1) acting as both selective TRPC inhibitors and tran-
1000 μm) to withstand high internal pressures, allowing flow
processing to be performed in a high-temperature/high-pressure
scription factor regulators of the nuclear factor of activated
T-cells (NFAT).6 One of these compounds, the trichloroacryl
regime, superheating solvents far above their boiling point,
sometimes reaching supercritical conditions.13 This feature can
derivative of pyrazole scaffold 1 (“Pyr 3”), specifically attenuates
activation of NFAT and hypertrophic growth in rat neonatal
be used to realize a central process intensification philosophy:14
the drastic acceleration of chemical processes at high tempera-
cardiomyocytes and in vivo pressure overload-induced cardiac
tures, where a reduction of reaction times from days to hours
hypertrophy in mice and therefore may also lead to the devel-
(or hours to minutes) is often possible, a feature shared with
opment of useful drugs for the safer therapeutic treatment of
pathological cardiac hypertrophy and heart failure.6,7 In addition,
the related 4-(pyrazol-1-yl)carboxanilide structural skeleton 2
has been implemented by pharmaceutical companies such as
Received: May 15, 2011
Published: July 01, 2011
r
2011 American Chemical Society
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Scheme 1. Bifurcated Synthesis Path to 4-(Pyrazol-1-yl)carboxanilides of Type 1 or 2 (Figure 1) Incorporating Hydrogenation/
Peptide Coupling (Path a) or BuchwaldꢀHartwig Amidation (Path b)
microwave chemistry in sealed vessels.15,16 Importantly, the
process window of microwave batch reactors (up to 300 °C
and 30 bar) employing sealed glass vessels is overlapping to a
great extent with the temperature/pressure regime of most
commercially available continuous flow reactors (200ꢀ350 °C
and up to 180 bar).13 As a consequence, microwave batch
reactors are ideal tools to initially optimize a chemical reaction
before moving to a high-temperature/high-pressure continuous
flow process (microwave-to-flow paradigm).17 As compared to
solely relying on flow equipment for the optimization step,18
using batch microwave technology allows a quick evaluation of a
large matrix of reaction conditions (different solvents, reagents,
etc.) in a very short time frame. In addition, problematic reaction
conditions (e.g., precipitation) are recognized at an early stage
before moving to flow conditions.
Herein we describe improved (process intensified) synthetic
protocols that allow the rapid multistep synthesis of 4-[tri-
fluoromethyl-(pyrazol-1-yl-)]carboxanilides of type 1 and 2
(Figure 1).6,8ꢀ10 These procedures are based on the use of
microwave batch or continuous flow chemistry as enabling
technologies to allow the reduction of reaction times from a
few days down to minutes.19
round-bottomed flask chemistry, and the overall reaction time
for the three steps is generally in the order of 2 days or more,
while the obtained overall yields range from 20% to 30% at
best.6ꢀ10 As a considerable additional improvement, we have
considered a BuchwaldꢀHartwig direct amidation starting
from a 1-(4-bromophenyl)-1H-pyrazole 7 as an attractive
alternative to the reduction/peptide coupling sequence
(Scheme 1, path b).
It was therefore one of our objectives to provide a simplified,
less time-consuming, and high-yielding procedure using a com-
bination of specifically tailored microwave-15,16 and microreac-
tion techniques11ꢀ13 for process intensification. All reactions
performed under flow conditions were optimized and adapted to
flow equipment by a series of preceding microwave batch
experiments.17
The use of multiple flow reaction devices in series, the
synthesis of complex molecules in “automated” fashion, is an
interesting approach whereby the product solutions generated by
individual flow reactors are not collected for isolation of inter-
mediates but directly fed to other flow reactors downstream of
the process.20 Key to this method is a very careful process design,
which has to ensure the compatibility of every individual flow
reaction with all other downstream steps.
Pyrazole Formation. For the generation of N-substituted
functionalized pyrazoles, a large number of synthetic procedures
is available.21 These methods are most commonly based on the
cyclocondensation of hydrazines with various bifunctional mol-
ecules such as 1,3-dicarbonyl compounds, R,β-unsaturated
ketones, and β-aminoenones, as well as 1,3-dipolar cycloaddition
reactions.21 Recently published approaches include, for example,
the cyclocondensation of N-arylhydrazones with nitroolefins in
ethylene glycol in the presence of air22 or the Pd-catalyzed four-
component reaction of a terminal alkyne, hydrazine (hydroxyl-
amine), CO, and an aryl iodide.23 Mori and co-workers have used
a well established protocol to prepare the starting nitro-substi-
tuted pyrazoles 6a,b in the three-step synthesis of 4-[5-tri-
fluormethyl-(pyrazol-1-yl-)]carboxanilides 1 and 2 (Figure 1),
employing enone 3a or 1,3-dicarbonyl compound 3b and
4-nitrophenylhydrazine as starting materials.6 Using controlled
microwave heating in sealed vessels as enabling technology,
’ RESULTS AND DISCUSSION
The known synthetic strategies for the preparation of 4-
(pyrazol-1-yl)carboxanilides generally pursue a pragmatic three-
step approach relying on standard procedures (Scheme 1, path
a), to generate small amounts of the target compounds for
biological screenings.6ꢀ10 Starting with a cyclocondensation
reaction between 4-nitrophenylhydrazine and an enone or 1,3-
dicarbonyl compound under acidic conditions, the resulting
1-(4-nitrophenyl)-1H-pyrazoles 6 are further reduced to the
corresponding anilines 8 in a catalytic hydrogenation (Pd/C)
step.6ꢀ10 For diversity generation, a large number of different
amides have been synthesized from the aniline and various
carboxylic acids using EDC/DMAP (or BOP/DIPEA; HBTU/
TEA)-based peptide coupling protocols.6ꢀ10 In a similar fashion,
acid chloride couplings have also been used in the final ami-
dation step.6ꢀ10 These methods are based on conventional
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Table 1. Optimized Conditions for the Microwave Batch Synthesis of 1H-Pyrazoles 6a,b and 7a,ba
a All reactions were performed in a single-mode microwave reactor (Monowave 300) using 10 mL Pyrex vials and magnetic stirring from the hydrazinium
salts on a ∼1ꢀ2.5 mmol scale except for 7a (30 mL vial, 10 mmol scale) with 1.05 equiv of 3 in 2 mL (20 mL) of solvent. b A switch from ethanol to the
1-propanol/water 3:1 (v/v) mixture displaying a slightly lower vapor pressure was necessary in order to stay below the pressure limit of around 30 bar of
the used microwave reactor.
we sought to drastically accelerate and simplify the published
protocols, which often require an overnight reflux to reach full
conversion.6ꢀ10
microwave heating of a 0.45 M suspension of 4-nitrophenyl-
hydrazinium chloride (4a) and enone 3a (1.05 equiv) in
ethanol at 160 °C for 2 min to afford pyrazole 6a in 82%
yield. For the envisaged flow implementation we switched to a
more dilute, homogeneous protocol (0.1 M) in methanol after
minor adjustments on temperature and time, obtaining a similar
yield. While the dehydration of intermediate 5 (R2 = CO2Et)
to the aromatic 4-ethoxycarbonyl-5-trifluormethyl-substituted
pyrazole ring in 6a worked sufficiently well under self-catalysis
by the liberated HCl, the replacement of the ester group by an
additional strongly electron-withdrawing CF3 group results in
the formation of a much more stable 4,5-dihydro-5-hydroxy-
pyrazole intermediate 5 (R2 = CF3).25 Addition of conc HCl
(3 equiv) was necessary to reach full conversion at 160 °C
toward pyrazole 6b (Table 1, entry 3). During our optimization
runs, we observed that for example the 4,5-dihydro-5-hydro-
xypyrazole intermediate 5 is almost the exclusively formed
product (HPLC/GCꢀMS), when performing the reaction at
lower temperature (100 °C, 5 min in DMF). However, com-
plete dehydration of the formed intermediate 5 into 3,5-bis-
(trifluoromethyl)-1H-pyrazole 6b could be achieved within
15 min by raising the reaction temperature to 205 °C (entry 4).
In a similar manner, the arylbromides 7a,b were prepared in
excellent yields (92ꢀ98%) using 4-bromophenylhydrazinium
chloride (4b) as starting material. DMF as solvent was found
With access to microwave reactors capable of superheating
organic solvents under carefully controlled internal temperature
monitoring conditions, this goal was easily achievable.24 An initial
modification of the original protocol6ꢀ10 was the replacement of
the typically employed combination of 4-nitrophenylhydrazine
base with H2SO4 or HCl acid with the more stable and commer-
cially available phenylhydrazinium chloride salts 4, thus eliminat-
ing the addition of an acid catalyst. The cyclocondensation
of both the enone 3a or 1,3-dicarbonyl compound 3b and
arylhydrazinium chloride salts 4 to the corresponding pyrazoles
is governed by the dehydration of the intermediate 4,5-dihydro-
5-hydroxypyrazole 5 (Table 1) as important kinetic bottleneck.25
Depending on the substrate, the dehydration generally required
relatively high temperatures and strongly acidic conditions to
reach full conversion within the intended time scale of a few
minutes. For both the 5-trifluoromethyl-1H-pyrazole as well as
the 3,5-bis(trifluoromethyl)-1H-pyrazole scaffolds (1 and 2,
Figure 1), we synthesized the corresponding 4-nitroaryl- and
4-bromoaryl-substituted derivatives 6 and 7 (Table 1). This
provided us with the possibility to pursue two different
amidation routes (Scheme 1), allowing diversity introduction
in the last step of the synthesis. Initial experiments involved
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Table 2. Optimized Conditions for the Continuous Flow Synthesis of 1H-Pyrazoles 6a,6b and 7a,7ba
a All reactions were performed in a stainless steel flow reactor (X-Cube Flash, Thales Nanotechnology Inc.) utilizing either a 4 mL (6a,b) or 8 mL (7a,b)
stainless steel coil (i.d. 1 mm) and a flow rate of 1.6ꢀ2.6 mL/min. For further details, see Experimental Section. b Isolated yields after flash
chromatography. c No isolated yield for compound 6b, instead the corresponding aniline 8b was obtained in 57% yield.
to solubilize both starting materials and product much better as
compared to ethanol and was therefore considered as the solvent
of choice in the preparation of pyrazole 7a (entry 5). Not un-
expectedly, the preparation of the respective electron-deficient
3,5-bis(trifluoromethyl)-1H-pyrazole 7b did again require sig-
nificantly higher temperatures (150 vs 100 °C for 5 min) and
HCl addition (10 equiv) to reach full conversion (entry 6). Aryl-
bromide 7b is a relatively volatile liquid and was thus prepared using
a solution of the starting materials in low boiling MeOH/H2O 2:1
(v/v) to facilitate isolation. After careful evaporation of the solvent,
7b was obtained in excellent yield (98%).
The application of microreactor technology for the generation
of heterocyclic compounds was recently reviewed.26 In this
context, it is worth mentioning that Seeberger and co-workers
have reported a three-step synthesis for the antiobesity drug
Rimonabant as an example for the continuous flow synthesis of a
prominent pyrazole drug.27 The set of conditions obtained in the
microwave experiments (Table 1) served as a good starting point
for the implementation into a flow regime, by and large fulfilling
the basic requirements for a continuous flow process of being
homogeneous and reaching completion within the envisaged
reaction time of less than 5 min. Bearing in mind the wide
operating window of the chosen stainless steel flow equipment
(up to 350 °C/180 bar),28 the generated protocols in batch were
clearly aimed at exploiting the merits of the exceptionally rapid
kinetics at high temperatures, resulting in reaction times of only
1ꢀ5 min, depending on the substrate.
All continuous flow experiments for the cyclocondensation
to pyrazoles were done in a stainless steel capillary microreactor
(1 mm i.d., X-Cube Flash, Thales Nanotechnology Inc.),28 to
which the premixed reaction mixture (0.1 M) was fed by an
HPLC pump while a constant inner pressure of 120ꢀ140 bar was
maintained. The stainless steel coil was protected from the
corrosive action of HCl by the addition of 1.05ꢀ2.0 equiv of
triethylamine and, where possible, by further minimization of
residence times.29 In contrast to the corresponding microwave
protocols (Table 1, entries 1 and 2), we switched from ethanol/
methanol to acetic acid as solvent, resulting in a significantly
higher yield for 6a as compared to the procedure using ethanol
relying solely on self-catalysis by the hydrazinium chloride salt
(91% vs 81%) (Table 2).
An important side reaction that can occur in microreactors
made of stainless steel is the reduction of nitro groups to the
corresponding amines (Bechamp reduction).29 Accordingly, our
initial experiments involving the reaction of enone 3a with
4-nitrophenylhydrazinium chloride (4a) in ethanol at 160 °C
and 5 min residence time showed 10% (HPLC-UV at 215 nm or
GCꢀMS) of the nitro compound being reduced to the corre-
sponding aniline derivative 8a. Further dilution of the reaction
mixture (0.1 f 0.02 M) and conducting the reaction at lower
temperatures (100ꢀ140 °C) were improper means to alleviate
the reducing effect of the stainless steel coil. We found that at the
used temperature of 160ꢀ175 °C a reduction of residence time
was the most effective measure in order to suppress the reduction
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to the aniline (8a) (14% after 5 min vs. 2% after 1.5 min). Thus,
we were able to synthesize the nitro-substituted pyrazole deri-
vative 6a at 175 °C and 1.5 min residence time in 91% yield after
flash chromatography (Table 2).
Nitro Group Reduction. The reduction of aliphatic and
aromatic nitro compounds to the corresponding amines is one
of the most frequently used synthetic processes in organic
chemistry, for which a plethora of methods is available.30 How-
ever, many well-known methods for the reduction of nitro
groups, such as catalytic hydrogenations, are difficult to imple-
ment into a microwave approach. The use of molecular hydrogen
in a catalytic hydrogenation is impeded by the difficulty of intro-
ducing hydrogen into the sealed reaction vessels of most
currently available microwave reactors.31 Although recently a
microwave accessory that allows performing catalytic hydro-
genations with externally supplied hydrogen gas was commer-
cialized,31,32 we favored a catalytic transfer hydrogenation because
of the simplified overall procedure.33 Recent examples include
the reduction of nitroarenes to anilines using a hydrazine
hydrate/FeCl3 mixture34 or Mo(CO)6/DBU in ethanol35 and
the reduction of aliphatic nitro groups using ammonium formate
and catalytic amounts of Pd/C in MeOH.36
However, the requirement of adding an acid scavenger such as
triethylamine and working with extremely short residence times
has its limits: for pyrazole 6b bearing an additional CF3 group, no
combination of temperature/residence time preventing the re-
duction to the aniline could be found. At the chosen conditions, a
temperature of >200 °C turned out to be essential to achieve
dehydration of the relatively electron-poor and thus quite stable
5-hydroxy-intermediate 5. We suspect that at these elevated
temperatures diffusion to the coil and reaction kinetics of the
reduction are very rapid and cannot be avoided any more by
reducing residence time. This assumption is supported by the
fact that in this case nitro compound 6b could not be isolated,
and instead only the corresponding aniline 8b was obtained in
57% yield (Table 2).
Bromide 7a was synthesized in 81% yield at 100 °C at a
residence time of 5 min employing DMF as solvent; this solvent
switch allows raising the substrate concentration to 0.5 M. The
analogous bromide 7b differing from 7a in having an additional
CF3 group did again require a higher reaction temperature
(230 °C) and acetic acid as solvent in order to achieve full
dehydration to the aromatic pyrazole ring. At the chosen con-
centration of 0.5 M, the addition of water in combination with an
increased amount of triethylamine (2 equiv) was needed to fully
homogenize the reaction mixture. Bromide 7b was obtained in
69% yield after flash chromatography (Table 2).
Our first optimization attempts were closely related to litera-
ture reports by groups from AMRI and GSK employing 1,4-
cyclohexadiene or 1-methyl-1-cyclohexene as hydrogen donor
for microwave-assisted catalytic transfer hydrogenations.33 How-
ever, these more reactive reagents can be replaced by less
expensive cyclohexene,33 which does not negatively affect the
transformation of the chosen substrates in terms of conversion or
selectivity. In an attempt to reduce the amount of catalyst and
hydrogen donor, we moved our initial protocol operating at
100 °C in ethanol toward a high-temperature regime at 160 °C.
We were pleased to see that this measure not only led to a
reduction in time from 10 to 2 min for substrate 6a but also
allowed a reduction in the amount of added Pd/C from 5% to 1%
while using 2 equiv of cyclohexene instead of 5 equiv. This
protocol furnished the corresponding anilines 8a (92%) and 8b
(96%) in high yield after isolation by flash chromatography.
In contrast to our preliminary batch microwave experiments,
the use of molecular hydrogen in the inherently safe process
environment of a flow hydrogenator was considered a particu-
larly attractive approach.37 The hydrogenation experiments in
continuous flow were done in a benchtop flow-hydrogenator
Scheme 2. Hydrogenation of 1-(4-Nitrophenyl)-1H-pyra-
zoles 6a,b under Microwave and Continuous Flow Conditions
Table 3. Screening of Reaction Conditions for the Continuous Flow Hydrogenation of 1-(4-Nitrophenyl)-1H-pyrazole 6a
(Scheme 2)
entry
catalyst (w/w%)
T (°C)
solvent/concn (mol/L)
flow rate (mL/min)
H2 pressurea (bar)
conversionb (%)
1
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pt/C
25
40
EtOH/0.02
EtOH/0.02
EtOH/0.02
EtOH/0.02
EtOH/0.02
EtOH/0.02
EtOH/0.02
EtOH/0.02
DMF/0.1
1
1
1
1
1
1
1
1
3
1
3
2.5
2
2
2
atm
atm
atm
atm
atm
atm
atm
atm
100
100
90
0
2
31
3
60
71
4
70
89
59 + 20c
5
25
6
10% Pd/Al2O3
10% Pd/Al2O3
10% Pd/Al2O3
10% Pd/Al2O3
RaNi
25
0
7
50
89
8
70
>99
>99
>99
>99
>99d
>99
>99e
86
9
70
10
11
12
13
14
15
70
DMF/0.1
RaNi
100
100
25
EtOH/0.03
EtOH/0.03
AcOH/0.03
AcOH/0.03
AcOH/0.03
RaNi
70
10% Pd/Al2O3
10% Pd/Al2O3
10% Pd/Al2O3
atm
atm
atm
40
100
a atm = H-Cube in “full H2” mode at atmospheric pressure; 70ꢀ100 bar = H-Cube in “controlled” mode. b Purity as measured by HPLC at 215 nm.
c Total percentage of byproducts. d 93% yield after isolation. e Free of impurity traces in HPLC at 215 nm.
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Scheme 3. Process Scheme and Reaction Conditions for the Synthesis of 1-(4-Aminophenyl)-1H-pyrazoles 8a,b under
Continuous Flow Conditionsa
(H-Cube, Thales Nanotechnology Inc.).38 The use of heteroge-
neous catalysts on a fixed catalyst bed has the advantage of circum-
venting the need for filtering off the catalyst, a feature of general
importance in the production of pharmaceuticals. Initially, a
thorough screening of different catalysts and reaction conditions
was performed in order to indicate a range of suitable conditions
for the reduction of nitro-compound 6a as substrate (Table 3).
Starting with 10% Pd/C, a 0.02 M substrate solution at 1 mL/min,
and temperatures up to 70 °C led to partial conversion into the
corresponding aniline (Table 3, entries 1ꢀ4), whereas 10% Pt/C
seemed to be more active but even at ambient temperatures was
too unselective (Table 3, entry 5). On the other hand, the
application of 10% Pd/Al2O3 as well as RaNi led to complete and
selective reduction of the nitro functionality under a variety of
temperatures and flow rates, employing either ethanol, DMF, or
acetic acid as solvents (Table 3, entries 6ꢀ15). Despite the lower
price of RaNi, 10% Pd/Al2O3 became our catalyst of choice in
combination with AcOH as a solvent, due to the incompatibility
of AcOH with RaNi. New reaction conditions were developed,
ranging from ambient to 80 °C (0.03 M), under which the nitro
group was fully converted, with temperatures in the range of
40ꢀ60 °C being most preferable for a clean process. At a flow
rate of 2 mL/min, this corresponds to a molar throughput of
3.6 mmol/h.
Two-Step Continuous Flow Synthesis of Amines 8a and
8b. Equipped with a set of optimized conditions, carefully designed
to ensure the compatibility of the initial pyrazole formation in
continuous flow with the subsequent flow hydrogenation as down-
stream reaction, our next goal was to join the two individual flow
steps to generate the amine precursors 8a and 8b without isolation
and purification of the corresponding nitro-substituted pyrazoles
6a,b (Scheme 3). Using both the X-Cube Flash coil reactor and
H-Cube hydrogenator under the previously optimized conditions
for the two individual steps of the cyclocondensationꢀhydrogena-
tion sequence (Table 2, Table 3), nitro compound 6a was gen-
erated at a reaction temperature of 175 °C and 1.5 min residence
time in acetic acid (0.1 M) as solvent (Table 1). The obtained
crude product solution was directly reduced in the flow hydro-
genator at 60 °C on 10% Pd/Al2O3 (Table 3), providing aniline 8a
in 86% yield after flash chromatography. As already mentioned, an
alternative synthesis path toward amine 8b arose from the inad-
vertent reduction of the formed nitro functionalized pyrazole 6b by
the stainless steel capillary material (Bechamp reduction).29 At the
preferred reaction temperature of 265 °C and a residence time of
1 min, the corresponding amine 8b was immediately generated
after in situ formation of 8b inside the stainless steel capillary and
was isolated in acceptable yield after flash chromatography (57%)
(Table 2).
Amidation. The amide function on the two pyrazole scaffolds
(Figure 1) is introduced in the last step of the synthesis and thus
is very well suited to diversify the molecule. In today’s chemical
literature there is a large variety of different amidation techni-
ques, of which carbodiimide-based peptide coupling protocols
are particularly attractive owing to the broad range of applicable
substrates and its high chemoselectivity.39 Ley and co-workers
have established a very versatile and clean continuous flow
method for the generation of di- and tripeptides using immobi-
lized peptide coupling reagents (PyBroP/HOBt) in combination
with catch and release strategies in a flow environment, with the
resulting benefit of greatly simplifying or even obviating
workup.40 Along similar lines, the Cosford group successfully
synthesized a range of imidazo[1,2-a]pyridine-2-carboxamides in
a glass-chip reactor using a homogeneous peptide protocol based
on EDC/HOBt in DMF and DIPEA as base.41
In the case of the desired 4-(pyrazol-1-yl)carboxanilides of
type 1 and 2, we have evaluated a variety of peptide coupling
conditions using both room temperature and microwave
protocols.42 Disappointingly, for all tested conditions the yields
of the anticipated coupling products were unsatisfactory (<30%).
Apparently, amine 8a and acids such as trichloroacrylic acid were
particularly unreactive substrates under these coupling conditions
(see structure 1a, Table 4). These findings are in agreement with
the low yield (35%) obtained by Mori and co-workers for the final
amidation step in the synthesis of the TRPC 3 channel inhibitor
1a (“Pyr 3”) using a room temperature peptide coupling protocol
(BOP/DIPEA in DMF).6
At this stage we considered a 2009 protocol by Nikem
Research that allows experimentally very straightforward micro-
wave-assisted amidations that simply involve heating aromatic
amines and carboxylic acids (aromatic, heteroaromatic, aliphatic) in
acetonitrile in the presence of 1 equiv of phosphorus trichloride.43
Applying 150 °C reaction temperature for 5 min high isolated
yields for a large variety of amide motifs were obtained.43 The fact
that this amidation protocol forms a suspension makes an im-
plementation into a flow process not feasible with currently
available flow equipment.
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Table 4. Isolated Yields for Carboxanilides 1a,b, 2aꢀe and Sulfonamides 10a,b Under Microwave Batch Conditionsa
a All reactions were performed in a single-mode microwave reactor (Monowave 300) using 10 mL Pyrex vials and magnetic stirring. Experiments were
made using anilines 8a,b on a 0.5 mmol scale with 1.1ꢀ1.5 equiv of carboxylic acid and 1.1ꢀ1.5 equiv of PCl3 in 2 mL of MeCN at 150 °C and 5 min
reaction time. Sulfonamides 10a,b were prepared on a 0.5 mmol scale using 1.5 equiv of the acid chloride and 100 μL of pyridine at 100 °C and 5 min
reaction time. b Isolated yields after flash chromatography.
In any event, using this simplified acid chloride coupling
method, the amidation of anilines 8a,b with a selection of both
electron-poor and electron-rich carboxylic acids was achieved in
a very convenient and straightforward manner. At a reaction
temperature of 150 °C, 5 min reaction time and acetonitrile as
solvent in a microwave batch experiment, we obtained a variety of
different amides in moderate to good yields (52ꢀ89%). Two
sulfonamides 10a,b were prepared in high yields (>90%) by
analogous sulfonyl chloride couplings under microwave condi-
tions at 100 °C and 5 min in acetonitrile/pyridine.
BuchwaldꢀHartwig Amidation. In order to further simplify
the synthesis not only by reducing reaction time but also by an
alternative two-step approach instead of the more traditional
three-step synthetic pathway, we briefly evaluated a cyclo-
condesation step involving a 4-bromophenylhydrazine species
followed by a Pd-catalyzed BuchwaldꢀHartwig amidation pro-
tocol to deliver the desired carboxanilides (Scheme 1, path b).
Having the cyclocondensation step already optimized under
microwave as well as under continuous flow conditions (see
above), we focused our efforts on the optimization of the CꢀN
cross-coupling process. Pd-catalyzed CꢀN bond-forming reac-
tions between aryl halides and amides as nucleophiles have
received broad interest in the past two decades.44 The versatility
of the substrates and tolerated functionalities has turned this
coupling into one of the most important reactions currently under
development. The BuchwaldꢀHartwig amidation process is im-
plemented into a wide range of fine chemical and natural product
syntheses as well as into drug discovery processes. Furthermore, a
plethora of transition-metal-catalyzed coupling reactions have
been successfully translated into high-speed microwave processes,
including BuchwaldꢀHartwig couplings.16 Notably, in a previous
project, we were able to successfully perform Pd-catalyzed N-
amidations on the somewhat related 4-(bromophenyl)-dihydro-
pyrimidine scaffold under microwave conditions.45
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Table 5. Microwave-Assisted BuchwaldꢀHartwig CꢀN Coupling Reactionsa
a All reactions were performed in a single-mode microwave reactor (Monowave 300) using 10 mL Pyrex vials and magnetic stirring. b Isolated yields after
flash chromatography.
Scheme 4. Process Scheme and Reaction Conditions for the Combined Continuous Flow/Microwave Batch Synthesis of Amides
1c,d and 2a,f
We thus decided to explore the scope of the Pd-catalyzed
version of the amide N-arylation reaction. Applying our pre-
viously optimized45 microwave conditions to the current sub-
strates [5 mol % Pd(OAc)2 as precatalyst, Xantphos as the
ligand, and Cs2CO3/THF as base/solvent combination at
150 °C and 15 min reaction time], a promising conversion of
nearly 87% was achieved. A successful microwave protocol was
developed by only slightly modifying this procedure in extend-
ing the reaction time to 30 min, otherwise keeping the remain-
ing reaction parameters unchanged. Further trials to change
the base, ligand, or solvent to additionally optimize the process
remained unsuccessful, delivering only partial conversion of
the 1-(4-bromophenyl)-1H-pyrazoles 7a,b. These aryl bro-
mides were effectively converted into the corresponding car-
boxanilides 1c,d and 2a,f in 56ꢀ92% yield after flash
chromatography (Table 5), therefore expanding the struc-
tural diversity of the desired 4-(pyrazol-1-yl)carboxanilides
scaffolds.
sonicated during the process. An attempt to translate our
optimized microwave conditions into a continuous flow proto-
col failed as a result of the restrictions of the available flow
equipment, as well as to the inhomogeneity of the reaction
mixture when using the optimized reaction conditions. Ulti-
mately, the two individually optimized steps (continuous flow
cyclocondensation and microwave batch BuchwaldꢀHartwig
amidation) were merged into one process, directly using the
product stream obtained in the initial flow cyclocondensation
step (Scheme 4). Applying the already optimized microwave
batch conditions allowed the isolation of the carboxamides 1c,d
and 2a,f in 45ꢀ70% overall yield after purification by flash
chromatography.
’ CONCLUSION
In conclusion, we have presented improved synthetic proto-
cols for the generation of pyrazole-derived inhibitors of TRPC3
of type 1 and 2 that can be easily scaled to multigram quantities
for pharmacological research purposes.47 Our methods rely on
the initial optimization of reaction conditions using sealed vessel
Very recently, continuous flow BuchwaldꢀHartwig reactions
have been demonstrated.46 To overcome solid bridging and
constriction disturbing the flow regime, the reactor coil was
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microwave synthesis as a process intensification technique. The
use of high-temperature/pressure conditions not only resulted
in a dramatic reduction of the required reaction and overall
processing times but also provided consistently better product
yields than the conventional methods. This new method will be
very useful for generating compound libraries of these (and
related) scaffolds, in particular considering the translation of the
method disclosed herein to a parallel microwave synthesis
approach. In addition, we have demonstrated that for strictly
homogeneous transformations the high-temperature microwave
conditions were readily transferable to a conventionally heated
continuous flow regime, which would in principle allow a
simple scale-up option to prepare larger quantities of com-
pounds. As an alternative to the original three-step method, a
two-step microwave-assisted protocol for the synthesis of 4-
(pyrazol-1-yl)carboxanilides that relies on a Pd-catalyzed Buch-
waldꢀHartwig amidation chemistry was also developed.
evaporation of the solvent, the residue was put on a silica column and
purified by flash chromatography to afford ethyl 1-(4-nitrophenyl)-
5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (6a) as a yellowish solid
(240 mg, 81%), mp 106ꢀ108 °C.6 1H NMR (300 MHz, DMSO-d6) δ
1.31 (t, J = 7.1 Hz, 3H), 4.44 (q, J = 9.0 Hz, 2H), 7.89 (d, J = 8.9 Hz, 2H),
8.39 (s, 1H), 8.43 (d, J = 9.0 Hz, 2H). MS (neg APCI): m/z (%) 330
(100) [M ꢀ 1].
Method B (entry 2, Table 1). To a solution of 4-nitrophenylhydrazine
hydrochloride (4a) (189.6 mg, 1 mmol) in methanol (10 mL) in a
30 mL Pyrex microwave vial was added ethyl 2-(ethoxymethylene)-
4,4,4-trifluoro-3-oxobutyrate (3a) (247.4 mg, 1.03 equiv). The mixture
was stirred/sonicated for 1 min and sealed with a snap-on cap. The
reaction mixture was subjected to microwave heating for 1.5 min (hold
time) at 175 °C and then cooled to 50 °C. After evaporation of the
solvent, the residue was purified by flash chromatography to afford ethyl
1-(4-nitrophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (6a) as
a yellowish solid (271 mg, 82%).
Continuous Flow Preparation. To a stirred solution of 4-nitro-
phenylhydrazine hydrochloride (4a) (189.6 mg, 1 mmol, 0.1 M) in
acetic acid (10 mL) in a cylindrical glass vessel were added ethyl
2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate (3a) (252.2 mg,
1.05 equiv) and triethylamine (106.3 mg, 1.05 equiv). After stirring/
sonication for 2 min, the homogeneous reaction mixture was subjected
to flow processing in the X-Cube Flash. A 4 mL stainless-steel coil was
mounted, and the instrument flushed with acetic acid at a constant flow
rate of 2.6 mL/min (1.5 min residence time) and a backpressure of 140
bar. After reaching the temperature set point of 175 °C, the inlet tubing
was quickly changed from the solvent reservoir to the sample vessel and,
after collection of the main fraction of the product mixture on the outlet,
placed back into the solvent reservoir for flushing the instrument
(∼5 min). The collected product solution (∼25 mL) was reduced
under vacuum, and the residue was purified by flash chromatography to
afford ethyl 1-(4-nitrophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-car-
boxylate (6a) as yellowish crystals (299 mg, 91%).
1-(4-Nitrophenyl)-3,5-bis(trifluoromethyl)-1H-pyrazole
(6b). Microwave Batch Preparation, Method A (entry 4, Table 1).
To a stirred mixture of 4-nitrophenylhydrazine hydrochloride (4a)
(171 mg, 0.9 mmol) and ethanol (2 mL) in a 10 mL Pyrex microwave
vial was added 1,1,1,5,5,5-hexafluoroacetylacetone (3b) (197 mg, 1.05
equiv) was added, followed by dropwise addition of conc HCl (300 μL,
4 equiv). The reaction vial was sealed with a snap-on cap, and the
suspension was subjected to microwave heating for 5 min (hold time)
at 160 °C and subsequently cooled to 50 °C. The so-formed yellow
reaction mixture was concentratedunder reducedpressure, and the residue
purified by flash chromatography (petrol ether/ethyl acetate 6:1) to afford
1-(4-nitrophenyl)-3,5-bis(trifluoromethyl)-1H-pyrazole (6b) as a yellow
oil (260 mg, 89%).8a 1H NMR (300 MHz, DMSO-d6) δ 7.94ꢀ7.98 (m,
3H), 8.45ꢀ8.49 (m, 2H). MS (pos APCI): m/z (%) 326 (100) [M + 1].
Method B (entry 5, Table 1). To a stirred solution of 4-nitrophenyl-
hydrazine hydrochloride (4a) (462.4 mg, 2.44 mmol) in n-propanol/
water 3:1 (v/v) (4 mL) in a 10 mL Pyrex microwave vial was added
1,1,1,5,5,5-hexafluoroacetylacetone (3b) (532.8 mg, 1.05 equiv). The
mixture was stirred/sonicated for 1 min, and the reaction vial was sealed
with a snap-on cap. The homogeneous reaction mixture was subjected to
microwave heating for 15 min (hold time) at 205 °C and then cooled to
50 °C. The reaction mixture was carefully reduced in vacuum (40 °C,
10 mbar), and the oil residue was taken up in 25 mL of diethyl ether,
washed with satd sodium bicarbonate (3 ꢁ 10 mL) and brine, and dried
over MgSO4. After evaporation of the diethylether, nitrophenyl-3,5-
bis(trifluoromethyl)-1H-pyrazole (6b) was obtained as a yellow oil
(688 mg, 87%).
’ EXPERIMENTAL SECTION
1
General Remarks. H and 13C NMR spectra were recorded on a
300 MHz instrument. Chemicalshifts (δ) are expressedin ppm downfield
from TMS as internal standard. The letters s, d, t, q, and m are used to
indicate singlet, doublet, triplet, quadruplet, and multiplet, respectively.
Low resolution mass spectra were either obtained on a LCꢀMS instru-
ment using atmospheric pressure chemical ionization (APCI) or electro-
spray ionization (ESI) in positive or negative mode. GCꢀMS monitoring
was based onelectronimpactionization (70eV) using a HP/5MS column
(30 m ꢁ 0.250 mm ꢁ 0.025 mm). After 1 min at 50 °C the temperature
was increased in 25 °C/min steps up to 300 °C and kept at 300 °C for
4 min. The carrier gas was helium, and the flow rate was 1.0 mL/min in
constant-flow mode. High-resolution mass spectra were recorded on a
FT-ICR-MS instrument using electrospray ionization (ESI) in positive
mode. Analytical HPLC analysis was carried out on a C18 reversed-phase
(RP) analytical column (150 ꢁ 4.6 mm, particle size 5 μm) at 25 °C using
a mobile phase A (water/acetonitrile 90:10 (v/v) + 0.1% TFA) and B
(MeCN + 0.1% TFA) at a flow rate of 1.0 mL/min. The following
gradient was applied: linear increase from solution 30% B to 100% B in
9 min, hold at 100% solution B for 1 min. All chemicals, solvents, catalysts,
and ligands were obtained from known commercial suppliers and were
used without any further purification. Microwave irradiation experiments
were carried out in a single-mode microwave instrument in Pyrex vials
using standard procedures.24 Reaction times refer to hold times at the
temperature indicated, not to total irradiation times. The temperature was
measured using the IR temperature sensor of the instrument. The flow
chemistry examples described herein were performed using a stainless
steel capillary microreactor and a flow hydrogenation reactor according to
established principles.28,38 The synthesized compounds were purified
using an automated chromatography system on cartridges packed with
KP-SIL, 60 Å (40ꢀ63 mmparticle size) and ethyl acetate (or ethyl acetate
containing 1% triethylamine for the purification of anilines 8a, 8b)/
petroleum ether mixtures as eluent. The purity of all synthesized
compounds (>98%) was either established by HPLC at 215 nm and/or
1H NMR spectroscopy. Melting points were determined on a standard
melting point apparatus and are uncorrected.
Ethyl 1-(4-Nitrophenyl)-5-(trifluoromethyl)-1H-pyrazole-
4-carboxylate (6a). Microwave Batch Preparation, Method A (entry
1, Table 1). To a stirred mixture of 4-nitrophenylhydrazine hydrochloride
(4a) (171 mg, 0.9 mmol) and ethanol (2 mL) in a 10 mL Pyrex microwave
vial was added ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate
(3a) (228 mg, 1.05 equiv). The reaction vial was sealed with a snap-on
cap, and the suspension was subjected to microwave heating for 2 min (hold
time) at 160 °C after which the reaction mixture was cooled to 50 °C. After
Ethyl 1-(4-Bromophenyl)-5-(trifluoromethyl)-1H-pyrazole-
4-carboxylate (7a). Microwave Batch Preparation (entry 5, Table 1).
To a stirred solution of 4-bromophenylhydrazine hydrochloride (4b)
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(1.88 g, 10 mmol) in DMF (20 mL) in a 30 mL Pyrex microwave vial
was added ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate (3a)
(2.52 g, 1.05 equiv). The mixture was stirred/sonicated for 1 min, and the
reaction vial sealed with a snap-on cap. The homogeneous reaction
mixture was subjected to microwave heating for 5 min (hold time) at
100 °C and then cooled to 50 °C. The reaction mixture was reduced in
vacuum (60 °C, 2 mbar), and DMF traces were removed azeotropically
(toluene) to afford ethyl 1-(4-bromophenyl)-5-(trifluoromethyl)-1H-
pyrazole-4-carboxylate (7a) as a pale yellow residue (3.33 g, 92%) or as
yellow needles after recrystallization in methanol/water 2:1 (v/v): mp
69ꢀ72 °C. 1H NMR (300 MHz, DMSO-d6) δ 1.30 (t, J = 7.2 Hz, 3H),
4.32 (q, J = 7.2 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 7.80 (d, J = 8.7, 2H), 8.31
(s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 14.3, 61.5, 116.82, 116.83,
119.3 (q, JCF = 269.4 Hz), 123.9, 128.7, 132.1 (q, JCF = 39.4 Hz), 138.6,
142.8, 160.7 ppm. HRMS (ESI) calcd for C13H11BrF3N2O2 362.9956
[M + H]+, found 362.9954
Continuous Flow Preparation. To a stirred solution of 4-bromophe-
nylhydrazine hydrochloride (4b) (0.752 g, 4 mmol, 0.5 M) in DMF
(8 mL) in a cylindrical glass vessel was added ethyl 2-(ethoxymethylene)-
4,4,4-trifluoro-3-oxobutyrate (3a) (1.01 g, 1.05 equiv) was added. After
stirring/sonication for 2 min, the homogeneous reaction mixture was
subjected to flow processing in the X-Cube Flash. A 8 mL stainless-steel
coilwas mounted, and the instrument was flushed withDMF at a constant
flow rate of 1.6 mL/min (5 min residence time) and a backpressure of 100
bar. After reaching the temperature set point of 100 °C, the inlet tubing
was quickly changed from the solvent reservoir to the sample vessel and,
after collection of the main fraction of the product mixture on the outlet,
put back intothe solvent reservoir for flushing theinstrument(∼ 10 min).
The product solution (∼25 mL) was reduced under vacuum, and DMF
traces were removed azeotropically (toluene), taken up in 30 mL of ethyl
acetate, washed with water (3 ꢁ 10 mL) and brine (3 ꢁ 10 mL), dried
over MgSO4, and evaporated to afford ethyl 1-(4-bromophenyl)-5-(tri-
fluoromethyl)-1H-pyrazole-4-carboxylate (7a) as a pale yellow residue
(1.174 g, 81%).
product mixture on the outlet, put back into the solvent reservoir for
flushing the instrument (∼10 min). The product solution (∼25 mL)
was diluted with 10 mL of brine and extracted with ethyl acetate (3 ꢁ
10 mL). After successive washings with satd sodium bicarbonate
(10 mL), water (3 ꢁ 10 mL) and brine, the organic phase was dried
over MgSO4 and evaporated carefully (40 °C, 2ꢀ5 mbar) to afford 1-(4-
bromophenyl)-3,5-bis(trifluoromethyl)-1H-pyrazole (7b) as a yellow-
brown oil (988 mg, 69%).
Catalyst Screening for the Continuous Flow Hydrogena-
tion of Nitro-Compound 6a (Table 3). All screenings were done in
the H-Cube continuous flow hydrogenator (Thales Nanotechnology
Inc.). Stock solutions of ethyl 1-(4-nitrophenyl)-5-(trifluoromethyl)-
1H-pyrazole-4-carboxylate (7a) in various polar solvents were prepared
(0.02ꢀ0.1 M in ethanol, DMF, acetic acid, as appropriate; see Table 3
for more details). Prior to every screening series, the instrument was
equipped with a fresh catalyst cartridge (10% Pd/C, 10% Pt/C, 10% Pd/
Al2O3, or RaNi). The desired values for the flow rate (1ꢀ3 mL/min), H2
pressure (“Full H2” atmospheric pressure up to 100 bar H2 overpressure),
and cartridge temperature (rtꢀ100 °C) were set on the input panel of the
instrument, and a constant flow of pure solvent was pumped through the
instrument until the system had stabilized at the chosen set points. At that
moment the inlet filter frit of the H-Cube was switched from the solvent
reservoir into the stock solution and the nitro-compound was pumped
into the H-Cube; simultaneously, the outlet was changed to a fresh 1 mL
HPLC vial. After processing ∼1 mL of stock solution, the inlet was again
changed to the solvent reservoir, a new set point (temperature, time, flow
rate) was programmed, the instrument was flushed with solvent until the
set points were reached, the inlet changed to the stock solution, and so
forth. The collected product solutions were subjected to HPLC analysis at
215 nm to determine conversions/purities (see Table 3).
Ethyl 1-(4-Aminophenyl)-5-(trifluoromethyl)-1H-pyrazole-
4-carboxylate (8a). Microwave Batch Preparation. To a stirred
mixture of ethyl 1-(4-nitrophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-
carboxylate (6a) (200 mg, 0.61 mmol) and ethanol (2 mL) in a 10 mL
Pyrex microwave vial was added cyclohexene (100 mg, 1.21 mmol,
125 μL), immediately followed by 10% (w/w) Pd/C (6.5 mg, 0.0061
mmol, 1 mol %). The reaction vial was sealed with a snap-on cap, and the
suspension was subjected to microwave heating for 2 min (hold time) at
160 °C and then cooled to 50 °C. After evaporation of the solvent, the
residue was subjected to flash chromatography to afford ethyl 1-(4-
aminophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (8a) as a
white solid (167 mg, 92%), mp 107ꢀ109 °C.6 1H NMR (300 MHz,
DMSO-d6) δ 1.28 (t, J = 7.1 Hz, 3H), 4.28 (q, J = 7.1 Hz, 2H), 5.61
(s, 2H), 6.63 (d, J = 8.7 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 8.17 (s, 1H).
MS (pos APCI): m/z (%) 300 (100) [M + 1].
1-(4-Bromophenyl)-3,5-bis(trifluoromethyl)-1H-pyrazole
(7b). Microwave Batch Preparation (entry 6, Table 1). To a stirred
solution of 4-bromophenylhydrazine hydrochloride (4b) (564.1 mg,
2.52 mmol) in methanol/water 2:1 (v/v) (3 mL) in a 10 mL Pyrex
microwave vial were added 1,1,1,5,5,5-hexafluoroacetylacetone (3b)
(655.4 mg, 1.05 equiv) and conc HCl (1 mL, ∼10 equiv). The mixture
was stirred/sonicated for 1 min, and the reaction vial sealed with a snap-
on cap. The homogeneous reaction mixture was subjected to microwave
heating for 5 min (hold time) at 150 °C and then cooled to 50 °C. The
solvent was carefully evaporated (40 °C, 2 mbar), and 1-(4-bromo-
phenyl)-3,5-bis(trifluoromethyl)-1H-pyrazole (7b) was either directly
obtained as a dark oil (895 mg, 99%) or further purified by flash
Continuous Flow Hydrogenation (entry 15, Table 3). A 0.03 M
solution of ethyl 1-(4-nitrophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-
carboxylate (6a) (148.2 mg, 0.45 mmol) in ethanol (15 mL) was
prepared. Using a fresh RaNi cartridge, the H-Cube was first flushed
with pure ethanol, while ramping to the desired set point (H2 “Con-
trolled” mode, 70 bar hydrogen overpressure, a flow rate of 2.5 mL/min
and a cartridge temperature of 100 °C). Next, the inlet of the H-Cube
was quickly changed from the solvent reservoir to the substrate solution,
and the outlet was simultaneously changed to a collection flask. After
processing the whole volume of starting material, the inlet was changed
back to the solvent reservoir, and the instrument was flushed with
a further 15ꢀ20 mL. After evaporation of the solvent, ethyl 1-(4-
aminophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (8a) was
obtained as yellowish residue (125 mg, 93%).
1
chromatography and obtained as a pale yellow oil (832 mg, 92%). H
NMR (300 MHz, DMSO-d6) δ 7.61 (d, J = 8.4, 2H) 7.82ꢀ7.85
(m, 3H); 13C NMR (75 MHz, DMSO-d6) δ 108.9, 119.2 (q, JCF
268.0 Hz), 120.9 (q, JCF = 267.4 Hz), 124.5, 128.8, 133.0, 134.2 (q, JCF
=
=
39.8 Hz), 137.3, 142.1 (q, JCF = 38.7 Hz) ppm; HRMS (ESI) calcd for
C11H6N2F6Br 358.9619 [M + H]+, found 358.9615
Continuous Flow Preparation. To a stirred solution of 4-bromo-
phenylhydrazine hydrochloride (4b) (0.752 mg, 4 mmol, 0.5 M) in
acetic acid/water 40:3 (8 mL of acetic acid + 0.6 mL of water) in a
cylindrical glass vessel were added 1,1,1,5,5,5-hexafluoroacetylacetone
(3b) (873.8 mg, 1.05 equiv) and triethylamine (809.5 mg, 2 equiv). After
stirring/sonication for 2 min, the homogeneous reaction mixture was
subjected to flow processing in the X-Cube Flash. An 8 mL stainless steel
coil was mounted, and the instrument was flushed with acetic acid at a
constant flow rate of 1.6 mL/min (5 min residence time) and a
backpressure of 140 bar. After reaching the temperature set point of
230 °C, the inlet tubing was quickly changed from the solvent reservoir
to the sample vessel and, after collection of the main fraction of the
4-(3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl)aniline (8b). Micro-
wave Batch Preparation. To a stirred mixture of 1-(4-nitrophenyl)-
3,5-bis(trifluoromethyl)-1H-pyrazole (6b) (355 mg, 1.1 mmol) and
ethanol (2 mL) in a 10 mL Pyrex microwave vial was added cyclohex-
ene (448 mg, 5.5 mmol, 554 μL), immediately followed by 10% (w/w)
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Pd/C (35 mg, 0.0033 mmol, 3 mol %). The reaction vial was sealed
with a snap-on cap, and the reaction mixture was subjected to
microwave heating for 5 min (hold time) at 150 °C and subsequently
cooled to 50 °C. After evaporation of the solvent, the residue was
subjected to flash chromatography (petrol ether/ethyl acetate + 1%
triethylamine 3:1) to afford 4-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-
yl)aniline (8b) as a white solid (312 mg, 96%), mp 140ꢀ142 °C; lit.48
130ꢀ133 °C.8a 1H NMR (300 MHz, DMSO-d6) δ 5.68 (s, 2H), 6.64
(d, J = 8.7 Hz, 2H), 7.16 (d, J = 8.6 Hz, 2H), 7.67 (s, 1H). MS (pos
APCI): m/z (%) 296 (100) [M+1].
Two-Step Continuous Flow Synthesis of Amines 8a,b
(CyclocondensationꢀReduction Sequence). Ethyl 1-(4-
Aminophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carbox-
ylate (8a). The optimized continuous flow-procedures for the indivi-
dual single-step preparations of 6a (X-Cube Flash, procedure as
disclosed in the single-step protocol) and 8a (H-Cube, procedure as
disclosed in the single-step protocol) were used to assemble a contin-
uous two-step flow protocol (1 mmol scale) without isolation of the
intermediate. According to the single-step procedure, 6a was prepared at
175 °C and a flow rate of 2.6 mL/min in a 4 mL stainless steel coil (1.5
min residence time) in acetic acid (0.1 M) with addition of 1.05 equiv of
triethylamine. The crude product solution exiting the X-Cube Flash
containing 6a was collected, diluted to 0.03 M concentration, and
directly pumped into the H-Cube. After hydrogenation of the crude
product solution in “Full H2” mode at 60 °C and a flow rate of 2 mL/min
using Pd/Al2O3 as catalyst, the collected product solution was reduced
under vacuum, brought onto a sample holder, and subjected to flash
chromatography (petrol ether/ethyl acetate + 1% triethylamine 3:1) to
afford ethyl 1-(4-aminophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-car-
boxylate (8a) as yellow crystals (259 mg, 86%).6
4-(3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl)aniline (8b).
To a stirred solution of 4-nitrophenylhydrazine hydrochloride (4a)
(189.6 mg, 1 mmol, 0.1 M) in acetic acid (10 mL) in a cylindrical glass
vessel were added 1,1,1,5,5,5-hexafluoroacetylacetone (3b) (214.3 mg,
1.03 equiv) and triethylamine (106.3 mg, 1.05 equiv). After stirring/
sonication for 2 min, the homogeneous reaction mixture was subjected
to flow processing in the X-Cube Flash. A 4 mL stainless-steel coil was
mounted, and the instrument was flushed with acetic acid at a constant
flow rate of 4 mL/min (1 min residence time) and a backpressure of 140
bar. After reaching the temperature set point of 265 °C, the inlet tubing
was quickly changed from the solvent reservoir to the sample vessel and,
after collection of the main fraction of the product mixture on the outlet,
put back into the solvent reservoir for flushing the instrument (∼5 min).
The collected product solution (∼25 mL) was reduced under vacuum
and subjected to flash chromatography (petrol ether/ethyl acetate + 1%
triethylamine 3:1) to afford 4-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-
aniline (8b) as an off-white solid (186 mg, 57%).8a
1.29 (t, J = 7.1 Hz, 3H), 4.31 (q, J = 7.1 Hz, 2H), 7.56 (d, J = 8.8 Hz, 2H),
7.80 (d, J = 8.8 Hz, 2H), 8.28 (s, 1H), 11.33 (s, 1H). MS (pos APCI): m/z
(%) 458 (100) [M + 1].
Ethyl 1-(4-(4-Methyl-1,2,3-thiadiazole-5-carboxamido)-
phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (1b)6,10c
.
White solid (180 mg, 78%), mp 119ꢀ120 °C; lit.10c mp 118ꢀ120 °C.
1H NMR (300 MHz, DMSO-d6) δ1.31 (t, J = 7.2, 3H), 2.83 (s, 3H),
4.32 (q, J = 7.2, 2H), 7.57 (d, J = 8.7, 2H), 7.88 (d, J = 8.7, 2H), 8.30 (s,
1H), 11.03 (s, 1H). MS (neg ESI): 424 (100) [M ꢀ 1].
N-(4-(3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-4-
chlorobenzamide (2a)9c. Off-white powder (215 mg, 86%), mp
195ꢀ197 °C (toluene); lit.9c mp 196ꢀ197 °C. H NMR (300 MHz,
1
DMSO-d6) δ 7.61ꢀ7.66 (m, 4H), 7.83 (s, 1H), 7.99ꢀ8.04 (m, 4H),
10.66 (s, 1H). MS (neg APCI): m/z (%) 432 (100) [M ꢀ 1].
N-(4-(3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-4-
methyl-1,2,3-thiadiazole-5-carboxamide (2b)9c. Brownish so-
lid (179 mg, 63%), mp 165ꢀ167 °C; lit.9c mp 164ꢀ166 °C. 1H NMR
(300 MHz, DMSO-d6) δ 3.25 (s, 3H), 7.64 (d, J = 8.7 Hz, 2H), 7.82
(s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 11.06 (s, 1H). MS (neg APCI): m/z
(%) 420 (100) [M ꢀ 1].
N-(4-(3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2,
3,3-trichloroacrylamide (2c)6. White solid (192 mg, 85%), mp
147ꢀ149 °C (toluene). 1H NMR (300 MHz, DMSO-d6) δ7.64 (d, J =
8.7, 2H), 7.82ꢀ7.85 (m, 3H), 11.35 (s, 1H). MS (neg ESI): 450 (100)
[M ꢀ 1].
N-(4-(3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)iso-
nicotinamide (2d)8a. White solid (101 mg, 89%), mp 170ꢀ172 °C;
lit.8a mp 156ꢀ157 °C. 1H NMR (300 MHz, DMSO-d6) δ7.64 (d, J =
8.7 Hz, 2H), 7.82 (s, 1H), 7.87ꢀ7.89 (m, 2H), 7.97ꢀ8.01 (m, 2H),
8.80ꢀ8.82 (m, 2H), 10.84 (s, 1H). MS (pos APCI): m/z (%) 401 (100)
[M + 1].
N-(4-(3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-3-
fluoroisonicotinamide (2e)9c. White solid (147 mg, 52%), mp
162ꢀ163 °C; lit.9c mp152ꢀ153 °C. 1H NMR (300 MHz, DMSO-d6) δ
7.64 (d, J = 8.7 Hz, 2H), 7.77 (t, J = 5.3 Hz, 1H), 7.84 (s, 1H), 7.92 (d, J =
8.7 Hz, 2H), 8.62 (d, J = 4.7, 1H), 8.79 (s, 1H), 11.06 (s, 1H). MS (neg
APCI): m/z (%) 417 (100) [M ꢀ 1].
Sulfonamides (10a,b). To a stirred mixture of 4-(3,5-bis-
(trifluoromethyl)-1H-pyrazol-1-yl)aniline (8b) (200 mg, 0.5 mmol)
and acetonitrile (2 mL) 10 mL Pyrex vial was added either 4-chlor-
obenzenesulfonyl chloride (158 mg, 0.75 mmol) or 4-methylbenzene-
sulfonyl chloride (142 mg, 0.75 mmol), followed by dropwise addition of
pyridine (100 μL). The reaction vial was sealed with a snap-on cap, and
the suspension was subjected to microwave heating for 5 min (hold
time) at 100 °C and then cooled to a temperature of 50 °C. The solvent
was evaporated, and the residue was subjected to flash chromatography
to obtain the pure products.
General Procedure for the Amidation of 4-(Pyrazol-1-
yl)anilines 8a,b to Carboxamides (1a,b; 2aꢀe) and Sulfona-
mides (10a,b) (Table 4). Carboxamides (1a,b; 2aꢀe). To a
stirred mixture of either ethyl 1-(4-aminophenyl)-5-(trifluoromethyl)-
1H-pyrazole-4-carboxylate (8a) (150 mg, 0.5 mmol) or 4-(3,5-bis-
(trifluoromethyl)-1H-pyrazol-1-yl)aniline (8b) (200 mg, 0.5 mmol)
and acetonitrile (2 mL) in a 10 mL Pyrex microwave vial was added
the selected carboxylic acid (0.55 mmol for 1b, 2c and 0.75 mmol for 1a,
2a, 2b, 2d) was added, followed by dropwise addition of phosphorus
trichloride (103 mg, 0.75 mmol, 66 μL). The reaction vial was sealed
with a snap-on cap, and the suspension subjected to microwave heating
for 5 min (hold time) at 150 °C and then cooled to a temperature of
50 °C. The solvent was evaporated, and the residue was subjected to
flash chromatography to obtain the pure products.
N-(4-(3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-4-
chlorobenzenesulfonamide (10a). White powder (211 mg, 90%),
mp 126ꢀ128 °C. 1H NMR (300 MHz, DMSO-d6) δ 7.29 (d, J = 8.7 Hz,
2H), 7.52 (d, J = 9 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 7.79 (s, 1H), 7.84
(d, J = 8.7 Hz, 2H) 10.91 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ
108.4, 119.1 (q, JCF = 267.9 Hz), 120.3, 120.9 (q, JCF = 270.0 Hz), 127.8,
129.1, 130.0, 133.7, 134.1 (q, JCF = 39.6 Hz), 138.5, 138.7, 140.0, 141.9
(q, JCF = 38.6 Hz) ppm; HRMS (ESI) calcd for C17H11O2N3F6SCl
470.0165 [M + H]+, found 470.0165.
N-(4-(3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-4-
methylbenzenesulfonamide (10b). White powder (225 mg,
92%), mp 105ꢀ107 °C. 1H NMR (300 MHz, DMSO-d6) δ2.34
(s, 3H), 7.24ꢀ7.29 (m, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.48 (d, J =
8.7 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.77 (s, 1H), 10.73 (s, 1H); 13
C
Ethyl 1-(4-(2,3,3-Trichloroacrylamido)phenyl)-5-(trifluoro-
methyl)-1H-pyrazole-4-carboxylate (1a)6. White solid (175 mg,
76%), mp 151ꢀ153 °C (toluene). 1H NMR (300 MHz, DMSO-d6) δ
NMR (75 MHz, DMSO-d6) δ 21.4, 108.4, 119.2 (q, JCF = 268.0 Hz),
119.8, 120.9 (q, JCF = 267.4 Hz), 127.2, 127.8, 130.3, 133.3, 134.1 (q, JCF
=
6667
dx.doi.org/10.1021/jo2009824 |J. Org. Chem. 2011, 76, 6657–6669

The Journal of Organic Chemistry
ARTICLE
39.5 Hz), 136.8, 140.5, 141.8 (q, JCF = 38.6 Hz), 144.2 ppm; HRMS (ESI)
calcd for C18H14O2N3F6S 450.0711 [M + H]+, found 450.0706.
General Procedure for the Direct Amidation via Buch-
waldꢀHartwig Pd-Cross-Coupling Reaction (Table 5). To a
stirred mixture of either ethyl 1-(4-bromophenyl)-5-(trifluoromethyl)-
1H-pyrazole-4-carboxylate (7a) (54.5 mg, 0.15 mmol) or 1-(4-bromo-
phenyl)-3,5-bis(trifluoromethyl)-1H-pyrazole (7b) (53.9 mg, 0.15
mmol) and THF (2 mL) in a 10 mL Pyrex microwave vial was added
benzamide (36.3 mg, 2 equiv) or 4-chlorobenzamide (46.7 mg, 2 equiv),
followed by addition of Xantphos (8.71 mg, 10 mol %), cesium
carbonate (97.8 mg, 2 equiv), and palladium acetate (1.7 mg, 5 mol %).
The reaction vial was sealed with a snap-on cap, and the suspension was
subjected to microwave heating for 30 min (hold time) at 150 °C and
then cooled to a temperature of 50 °C. The solvent was evaporated, and
the residue was subjected to flash chromatography to obtain the pure
products.
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Ethyl 1-(4-Benzamidophenyl)-5-(trifluoromethyl)-1H-pyr-
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1
212ꢀ214 °C. H NMR (300 MHz, DMSO-d6) δ 1.01 (t, J = 6.9 Hz,
3H), 4.33 (q, J = 7.2 Hz, 2H), 7.52ꢀ7.63 (m, 5H), 7.97ꢀ8.00 (m, 4H),
8.29 (s, 1H) 10.57 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 14.4, 61.5,
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116.5, 119.5 (JCF = 269.4 Hz), 120.8, 127.0, 128.2, 128.9, 131.9 (JCF
=
39.2 Hz), 132.3, 134.5, 135.1, 141.2, 142.5, 160.8, 166.4 ppm; HRMS
(ESI) calcd for C20H17O3N3F3 404.1222 [M + H]+, found 404.1218.
Ethyl 1-(4-(4-Chlorobenzamido)phenyl)-5-(trifluoromethyl)-
1H-pyrazole-4-carboxylate (1d)9d. White powder (37 mg, 56%),
mp 189ꢀ191 °C; lit.9d mp 201ꢀ202 °C. 1H NMR (300 MHz, DMSO-
d6) δ 1.31 (t, J = 7.2 Hz, 3H), 4.32 (q, J = 7.2 Hz, 2H), 7.52ꢀ7.66 (m,
4H), 7.95ꢀ8.00 (m, 4H), 8.29 (s, 1H) 10.62 (s, 1H). MS (neg APCI):
m/z (%) 436 (100) [M ꢀ 1].
N-(4-(3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-4-
chlorobenzamide (2a)9c. White powder (60 mg, 92%), mp 195ꢀ
197 °C (toluene); lit.9c mp 196ꢀ197 °C. 1H NMR (300 MHz, DMSO-
d6) δ 7.60ꢀ7.65 (m, 4H), 7.83 (s, 1H), 7.99ꢀ8.03 (m, 4H), 10.65
(s, 1H). MS (neg APCI): m/z (%) 432 (100) [M ꢀ 1].
N-(4-(3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-
benzamide (2f). White powder (55 mg, 92%),10c mp 238ꢀ240 °C;
1
lit.10c mp 243ꢀ245 °C. H NMR (300 MHz, DMSO-d6): 7.53ꢀ7.68
(m, 5H), 7.81 (s, 1H), 7.97ꢀ8.03 (m, 4H), 10.60 (s, 1H). MS (neg ESI):
398 (100) [M ꢀ 1].
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’ ASSOCIATED CONTENT
S
Supporting Information. Copies of NMR spectra and
b
compound characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
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Gustafson, T.; Seeberger, P. H. Synlett 2009, 2382. (b) Hartman, R. L.;
Jensen, K. F. Lab Chip 2009, 9, 2495. (c) Mak, X. Y.; Laurino, P.;
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Corresponding Author
*E-mail: toma.glasnov@uni-graz.at; oliver.kappe@uni-graz.at.
’ ACKNOWLEDGMENT
This work was supported by a grant from the Christian
Doppler Research Society (CDG).
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