One-Pot Two-Step Synthesis of Isochromene-Fused CF3-Substituted Pyrazoles

Article abstract of DOI:10.1002/ejoc.202000942

An efficient one-pot, two step method for fusing two biologically active motifs, CF₃-substituted pyrazoles and isochromenes, was developed. Selective O-benzylation of CF₃-substituted pyrazolones and subsequent Pd-catalyzed direct C–H arylation generate a fused tricycle. For the synthesized compounds through-space ¹³C–¹⁹F spin–spin coupling was revealed. In addition, the synthesis of three thioisochromene analogues, and one isocoumarin derivative, was accomplished.

Full text of DOI:10.1002/ejoc.202000942

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: One-Pot Two-Step Synthesis of Isochromene-Fused CF3-
Substituted Pyrazoles
Authors: Andrea M. Nikolić, Filip Živković, Života Selaković, Peter Wipf,
and Igor Opsenica
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000942
Link to VoR: https://doi.org/10.1002/ejoc.202000942
01/2020

10.1002/ejoc.202000942
European Journal of Organic Chemistry
COMMUNICATION
One-Pot Two-Step Synthesis of Isochromene-Fused CF3-
Substituted Pyrazoles
Andrea M. Nikolić,[a] Filip Živković,[a] Života Selaković,[a] Peter Wipf,[b] and Igor M. Opsenica*[a]
[a]
A. M. Nikolić , F. Živković, Ž. Selaković, Prof. Dr. I. M. Opsenica
University of Belgrade – Faculty of Chemistry
PO Box 51, Studentski trg 16, 11158 Belgrade, Serbia
E-mail: igorop@chem.bg.ac.rs
http://chem.bg.ac.rs/osoblje/76-en.html
P. Wipf
[b]
Department of Chemistry,
University of Pittsburgh
219 Parkman Avenue, Pittsburgh, PA 15260, USA
Supporting information for this article is given via a link at the end of the document.
Abstract: An efficient one-pot, two step method for fusing two
biologically active motifs, CF3-substituted pyrazoles and
isochromenes, has been developed. Selective O-benzylation of CF3-
substituted pyrazolones and subsequent Pd-catalysed direct C–H
arylation generate a fused tricycle. For the synthesized compounds
through-space 13C–19F spin–spin coupling was revealed. In addition,
the synthesis of three thioisochromene analogues, and one
isocoumarin derivative, was accomplished.
This is illustrated with approved drugs such as celecoxib[3a] and
mavacoxib[3b] (COX-2 inhibitors with anti-inflammatory activity)
and razaxaban[3c] (an anticoagulant). Additionally, many other
molecules
containing
the
CF3-pyrazole
substructure
demonstrate promising activity,[4] an example being SC-560, a
COX-1 inhibitor, which acts as a growth inhibitor of human lung
cancer cells[4a] (Figure 1). Accordingly, it comes as no surprise
that the synthesis of trifluoromethylated pyrazoles has recently
been extensively studied.[5]
Isochromenes are another privileged structural motif present in
many natural products and bioactive molecules (Figure 1).[6]
Pyrazoles are an important class of five-membered nitrogen-
containing heterocyclic compounds that have found diverse
applications in the pharmaceutical industry, coordination
chemistry, food processing, and materials research.[1] The
introduction of a trifluoromethyl (CF3) group into a molecule can
significantly improve the biological properties of
a drug
candidate,[2] and as such trifluoromethylated pyrazoles show a
great potential as pharmaceutical agents (Figure 1).
Scheme 1. Strategies for the synthesis of 3-phenyl-1-(trifluoromethyl)-3,5-
dihydroisochromeno[3,4-c]pyrazole 4a
Figure 1. CF3-substituted pyrazoles and isochromenes as privileged scaffolds.
1
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10.1002/ejoc.202000942
European Journal of Organic Chemistry
COMMUNICATION
Chloroquinocin is an antibiotic isolated from Streptomyces
culture LL-A9227 and was found to exhibit antimicrobial activity
against Gram-positive bacteria.[7a] Tazettine is a metabolite
isolated from Pancratium canariense Ker-Gawl (Amaryllidaceae),
monosubstituted o-bromobenzyl-bromides, including an example
with a Cl substituent (4d).
an ornamental plant found in the Canary Islands (Figure 1).[7b]
synthetic fusion of
A
a
CF3-substituted pyrazole with an
isochromene is therefore appealing (Figure 1),[2d,6] and we
sought the opportunity to explore the synthetic approach to
generate this fused tricycle. Our approach to obtain these new
hybrid structures relied on a sequence of two reactions. Starting
from CF3-substituted pyrazolones, a selective O-benzylation and
subsequent Pd-catalyzed intramolecular C-H arylation provided
the desired 3,5-dihydroisochromeno[3,4-c]pyrazole moiety
(Scheme 1). The direct C–H arylation of pyrazolones has
recently been thoroughly reviewed.[8] The reactivity of pyrazoles
in Pd-catalyzed C–H bond arylations follows the order C5>C4≫
C3. Even though the intermolecular direct arylation of pyrazoles
has been extensively explored, there are still only a few
intramolecular direct arylation methods available. The
intramolecular direct arylation of pyrazoles at positions C4[9] and
C5[10], respectively, was reported in the synthesis of condensed
systems. To improve the usefulness of our methodology we
developed
a one-pot sequence of O-benzylation and Pd-
catalyzed intramolecular direct C–H arylation.
Prior to optimizing for a one-pot protocol, we performed a two-
step coupling procedure and isolated the ether intermediate 3a
(Scheme 1a). Pyrazolone 1a was alkylated with benzyl-bromide
2a in the presence of K2CO3 and DMF as solvent at room
temperature. The reaction progress was followed by TLC, and
after 1 h complete consumption of 1a was observed. To our
delight the product 3a was isolated in near-quantitative yield
after dry-flash chromatography on SiO2. For the formation of the
isochromene ring, 3a was heated at 120 ºC in DMF in the
presence of pre-generated Pd-catalyst and K2CO3 in inert
atmosphere. The reaction was complete after 1 h (as suggested
by TLC analysis), and the product 4a was isolated in 82% yield
after dry-flash chromatography on SiO2 (Scheme 1a).
Subsequently, we investigated the tandem approach (Scheme
1b) and one-pot two-step methodology (Scheme 1c) for the
synthesis of 4a. At first, we added all the reagents at once in
inert atmosphere and then stirred the reaction mixture at room
temperature until 1a had disappeared (30 min according to TLC
analysis). Next, the reaction mixture was heated at 120 ºC until
3a had been consumed (4.5 h, as monitored by TLC analysis).
The desired product 4a was isolated in 80% yield (Scheme 1b).
Due to the longer reaction time and slightly lower yield in the
tandem approach, our next modification was to explore the one-
pot two-step procedure. After reacting 1a and 2a in DMF in the
presence of K2CO3 at room temperature for 1 h, in order to
generate 3a, pre-prepared Pd-catalyst and K2CO3 were added
and the reaction mixture was heated at 120 ºC until 3a was
completely converted into 4a (1 h, as monitored by TLC
analysis). After purification, 4a was isolated in 82% yield
(Scheme 1c). Since the one-pot two-step method produced a
higher yield in a shorter reaction time, we chose this procedure
for our further experiments. Notably, compound 4a was also
synthesized on 1-mmol scale in 78% yield (Scheme 1c).
Scheme 2. Two step synthesis of tricyclic 3,5-dihydroisochromeno[3,4-
c]pyrazoles. General procedure: Reactions were performed with 1 (1 equiv), 2
(1.05 equiv), K2CO3 (2 equiv) in dry DMF (1.5 mL per 0.26 mmol of 1) at r.t.,
and with subsequent adding of [Pd(PPh3)4] (10 mol % Pd) in dry DMF (0.5 mL)
at 120 °C. Isolated yields are shown. For detailed experimental procedures,
see the SI.
Reactions with benzyl bromides containing substitutents
commonly found in natural products
– dioxolanes and o-
dimethoxy groups – yielded products 4e and 4f in moderate
yields (Scheme 2), presumably due to the formation of side-
products by oxidation of the electron-rich phenyl ring. Next, we
explored the reaction with different substituents on the phenyl
ring attached to the N1 atom. The desired products with Me- and
F-substituents, i.e. 4g and 4h, were isolated in good yields (82%
and 70%), while the pyrazolone with the NO2-substituent
provided product 4i in 48% yield (Scheme 2).
In order to further examine the scope of our methodology,
compounds 4b-4k were synthesized for the first time using the
one-pot two-step approach (Scheme 2). Good yields of the
desired products (4b-4d) were obtained from several
Interestingly, a more detailed analysis of the 13C NMR spectra of
products 4a-4i containing the CF3-group revealed that the peak
2
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10.1002/ejoc.202000942
European Journal of Organic Chemistry
COMMUNICATION
for the carbon atom from the benzyl bromide substituent (C in
the ortho-position to the C attached to the pyrazole ring) did not
form a singlet but rather a quartet (J ~ 4 Hz). This can be
explained either by a long-range (5-bond) 13C-19F coupling or a
through-space 13C–19F spin–spin coupling. As 5-bonds couplings
are rare and through-space 13C–19F coupling have previously
been reported,[11] we concluded that the latter explanation was
more likely (Figure 2, see also SI).
issue with regioselectivity has been documented to arise in the
alkylation reactions under aprotic conditions.[13] Consequently, it
did not come as a surprise when we faced a similar problem with
some of the substrates in the benzylation step in our synthesis.
Obviously, the outcome of the benzylation step is mostly
affected by the electronic effect of the substituent in the C3
position of the pyrazole.
We were pleased to find that using a direct Pd-catalyzed C–H
arylation, the corresponding thionated analogues 6a, 6b and 6c
could be obtained in moderate to good yields (Scheme 4). The
precursors of 6a-c, 5a-c were synthesized in two steps starting
from pyrazolones 1a, 1e and 1f. Firstly, the pyrazolones were
transformed into the thio derivatives using Lawesson’s reagent,
and the thiopyrazolones were then reacted with 2a in order to
obtain thioethers 5a-c (See SI). The isothiochromene cores of
6a-c were than constructed from 5a-c in the presence of
Pd(OAc)2, PPh3, K2CO3 and DMF at 120 ºC in 67%, 75% and
77% yield, respectively.
Figure 2. C‒F through-space (J = 4 Hz) and NOESY correlations in 4e.
We also attempted to expand our methodology to Me- and Ph-
substituted pyrazoles. Compounds 1a and 1f were transformed
into compounds 4j and 4k in 30% and 63% yield, respectively
(Scheme 2). Since these yields were significantly lower
compared to the CF3-analogue 4a, we further investigated the
cause of limitation in scope (Scheme 3). We performed a
benzylation of 1e and 1f and, beside the desired products, we
identified several side products, most likely dibenzylated
regioisomers (See SI). Furthermore, we separately performed a
Pd-catalyzed direct arylation on the O-benzylated intermediates
3b and 3c and found that this step proceeded in excellent yield
(Scheme 3). Compounds 4j and 4k were isolated in 99% and
80% yield starting from compounds 3b and 3c, respectively.
Therefore, we concluded that the benzylation reaction was the
problematic step of the sequence.
Scheme 4. Synthesis of dihydroisothiochromeno[3,4-c]pyrazole derivatives
6a-c.
Finally, we envisioned that this methodology could be further
expanded for the synthesis of isochromeno[3,4-c]pyrazol-5(3H)-
ones, containing another motif commonly encountered in natural
products. Utilizing a previously reported procedure for the
oxidation of benzylic position, substrate 4a was treated with
PCC in dry CH2Cl2, and the desired oxidized product 7a was
obtained in 30% yield with 54% recovery of starting material
(Scheme 5). The product yield is consistent with the previously
reported methods.[14]
O
PCC, Celite
CH2Cl2, , 24 h
O
O
N
N
N
N
30%, 54% rsm
CF3
4a
CF3
7a
Scheme 5. Synthesis of isochromeno[3,4-c]pyrazol-5(3H)-ones 7a.
In conclusion, we have developed an efficient one-pot two-step
methodology for combining two privileged motifs, CF3-
substituted pyrazolone and isochromene, into one hybrid
Scheme
3.
Two-step
synthesis
of
and
1-methyl-3-phenyl-3,5-
1,3-diphenyl-3,5-
molecule. We have utilized
a sequence of reactions, the
dihydroisochromeno[3,4-c]pyrazole
dihydroisochromeno[3,4-c]pyrazole
regioselective O-benzylation of CF3-substituted pyrazolones and
the Pd-catalyzed C–H direct arylation, to obtain the tricyclic
fused ring system. It is worth mentioning that we have observed
an interesting and rare through-space 13C–19F spin–spin
coupling in the NMR spectra of the synthesized compounds. The
oxidation of the benzylic position of the isochromene subunit
opens the possibility for the synthesis of isochromeno[3,4-
The deprotonated pyrazolone is essentially an enolate, capable
of acting as an ambident nucleophile with the C4, N2 and O-
atoms of the pyrazolone as nucleophilic sites.[12] Accordingly, an
3
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10.1002/ejoc.202000942
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Braun, Á. G. Ravelo, M. Del Arco-Aguilar, M. López, J. Nat. Prod. 2009,
72, 112.
c]pyrazol-5(3H)-ones, containing another typical natural product
moiety. Finally, we have also succeeded in synthesizing three
thioisochromene analogues in three steps. Evaluation of
biological activity of the synthesized compounds and potential
pharmaceutical application is currently under exploration in our
laboratory.
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This research was financially supported by the Ministry of
Education, Science and Technological Development of Serbia
(Contract number: 451-03-68/2020-14/200168), and Serbian
Academy of Sciences and Arts under strategic projects
programme - grant agreement No. 01-2019-F65. The authors
acknowledge the support of the FP7 RegPot project FCUB ERA
GA No. 256716. The EC does not share responsibility for the
content of the article.
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Keywords: pyrazoles • isochromenes • heterocycles • C‒F
through-space correlation • palladium
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4
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Entry for the Table of Contents
An efficient one-pot, two step method for fusing two biologically active motifs, CF3-substituted pyrazoles and isochromenes, has been
developed.
Institute and/or researcher Twitter usernames: @OpsenicaLab
5
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