Published: July 01, 2011
r 2011 American Chemical Society 6657 dx.doi.org/10.1021/jo2009824 | J. Org. Chem. 2011, 76, 6657–6669
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
b
S Supporting Information
’ 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
inhibitors, in addition to anti-estrogens acting as potential
antitumor therapeutics.3 The past decade brought the discovery
of a new class of drugs targeting the Na+/Ca2+ signaling path-
ways, which play a key role in many pathogenic processes
including systemic diseases, inflammation, and cancer.1,4 One
important topic in this rapidly growing field are drugs which are
tuning the activity of canonical transient receptor potential
channels (TRPC), controlling the influx of intracellular Ca2+
into a plethora of mammalian cell types.5 Mori and co-workers
recently described a number of 4-(pyrazol-1-yl)carboxanilides
(Figure 1) acting as both selective TRPC inhibitors and tran-
scription factor regulators of the nuclear factor of activated
T-cells (NFAT).6 One of these compounds, the trichloroacryl
derivative of pyrazole scaffold 1 (“Pyr 3”), specifically attenuates
activation of NFAT and hypertrophic growth in rat neonatal
cardiomyocytes and in vivo pressure overload-induced cardiac
hypertrophy in mice and therefore may also lead to the devel-
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
Abbott,8 Astellas,9 and Boehringer-Ingelheim10 into the devel-
opment of discovery libraries in the search for potential lead
compounds in these areas.7
Today, performing organic synthesis under continuous flow
conditions is getting widely accepted in both industry and
academia, while at the same time the available technology is
getting more mature.11,12 One of the important features of flow
reactors is the ability of the used capillaries or channels (∼50

1000 μm) to withstand high internal pressures, allowing flow
processing to be performed in a high-temperature/high-pressure
regime, superheating solvents far above their boiling point,
sometimes reaching supercritical conditions.13 This feature can
be used to realize a central process intensification philosophy:14
the drastic acceleration of chemical processes at high tempera-
tures, where a reduction of reaction times from days to hours
(or hours to minutes) is often possible, a feature shared with
Figure 1. Pyrazole-based family of TRPC inhibitors/NFAT transcrip-
tion factor regulators.6
10
Received: May 15, 2011
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 Buchwald
Hartwig amidation with
carboxylic acid amides.

6658 dx.doi.org/10.1021/jo2009824 |J. Org. Chem. 2011, 76, 6657–6669
The Journal of Organic Chemistry ARTICLE
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 (200
350
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).6,8
10 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
’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.6
10 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.6
10 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.6
10 In a similar fashion,
acid chloride couplings have also been used in the final ami-
dation step.6
10 These methods are based on conventional
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.6
10 As a considerable additional improvement, we have
considered a Buchwald
Hartwig 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 techniques11
13 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.23Mori 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,
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 Buchwald
Hartwig Amidation (Path b)