Synthesis of diversely 1,3,5-trisubstituted pyrazoles via 5-exo-dig cyclization

Article abstract of DOI:10.1039/c2ob25580d

5-Exo-dig cyclocondensation of alk-3-yn-1-ones with hydrazines, in the presence of montmorillonite K-10, provides an effective method with a high atom economy for the synthesis of diversely 1,3,5-trisubstituted pyrazoles. The microwave-accelerated reaction proceeds in the absence of solvent and leads to 5-benzyl substituted pyrazoles with good yields (72-91%). The regiochemistry of the process was confirmed by the X-ray crystallographic structure determination of 1-(2-fluorophenyl)-5-(4-methylbenzyl)-3-phenyl-1H-pyrazole.

Full text of DOI:10.1039/c2ob25580d

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Synthesis of diversely 1,3,5-trisubstituted pyrazoles via 5-exo-dig cyclization†
Dmitry A. Borkin,a Mirela Puscau,b Alena Carlson,a Agnes Solan,b Kraig A. Wheeler,c Béla Török*a and
Roman Dembinski*b
Received 18th March 2012, Accepted 1st May 2012
DOI: 10.1039/c2ob25580d
N-myristoyltransferase,5 cancer kinases,6 and one of the most
5-Exo-dig cyclocondensation of alk-3-yn-1-ones with hydra-
active histone deacetylase (HDAC8) inhibitors.7
zines, in the presence of montmorillonite K-10, provides an
Although a variety of methodologies and protocols have been
reported, the development of contemporary synthetic routes that
allow the regionselective assembly of substituted pyrazoles from
simple, readily available starting materials, still remains an
important objective.
Substituted pyrazoles are commonly accessed via ring deriva-
tization, addition or cyclization of acyclic precursors.8 The latter
one includes the variety of oxygen-containing substrates. In a
classical reaction, hydrazine, and alkyl- or arylhydrazines
undergo cyclocondensation with 1,3-dicarbonyl compounds to
give pyrazoles. However, the use of unsymmetrical 1,3-diketones
gives a mixture of regioisomers. In addition, most traditional
methods require two steps; a cyclization and a subsequent aro-
matization (oxidation). Several advances have recently been
reported including a synthesis starting from alk-2-yn-1-ones9 or
a continuous flow protocol.10,11
Pyrazoles containing benzyl groups were recently investigated
and proved to be potent, selective, and orally active human glu-
cagon receptor antagonists.12 The synthesis of 5-benzyl substi-
tuted compounds has been achieved through a cyclization
reaction of a diketone 2 with a hydrazine. Not surprisingly two
regioisomers 3 and 4 were formed with 45% and 36% yield,
respectively (Scheme 1) and had to be separated. Similarly, in a
reaction of 1,3-diynes with phenylhydrazine, the two regio-
isomers were obtained in 20% and 28% yield.13
effective method with a high atom economy for the synthesis
of diversely 1,3,5-trisubstituted pyrazoles. The microwave-
accelerated reaction proceeds in the absence of solvent and
leads to 5-benzyl substituted pyrazoles with good yields
(72–91%). The regiochemistry of the process was confirmed
by the X-ray crystallographic structure determination of
1-(2-fluorophenyl)-5-(4-methylbenzyl)-3-phenyl-1H-pyrazole.
The pyrazole moiety is present in many important agrochemical
and pharmaceutical products, such as the pesticides Cyenopyra-
fen, Tebufenpyrad, Tolfenpyrad, Fenpyroximate, and non-
steroidal anti-inflammatory drug Celecoxib (Celebrex, 1a,
Fig. 1). Deracoxib (Deramaxx, 1b) is a marketed agent for the
treatment of inflammation and pain for dogs. In addition, pyra-
zoles are used as anticancer agents,1 show anti-inflammatory and
molluscicidal activity,2 are cannabinoid-1 receptor (CB1R) in-
verse agonists for the treatment of obesity,3 cyclooxygenase-2,4
Alk-3-yn-1-ones (propargyl ketones, 5)14 are proven versatile
bifunctional materials for the synthesis of five-membered hetero-
cycles. Their cycloisomerization and related electrophilic cycli-
zation reactions lead to substituted furans.15,16 Continuing our
efforts on the development of synthetic methods,17 herein regio-
selective synthesis of trisubstituted pyrazoles is described.
Fig. 1 Examples of biologically active pyrazoles.
aDepartment of Chemistry, University of Massachusetts Boston, 100
Morrissey Blvd., Boston, MA 02125, USA. E-mail: bela.torok@umb.edu
bDepartment of Chemistry, Oakland University, 2200 N. Squirrel Rd.,
Rochester, Michigan 48309-4477, USA. E-mail: dembinsk@oakland.edu
cDepartment of Chemistry, Eastern Illinois University, 600 Lincoln
Avenue, Charleston, Illinois 61920-3099, USA
†Electronic supplementary information (ESI) available: 1H and 13C
NMR spectra for pyrazoles 3a–j. CCDC 866543. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
c2ob25580d
Scheme 1 Synthesis of pyrazoles 3 and 4 via cyclocondensation of
diketone 2 and hydrazine.
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Table 1 Catalyst optimization for cyclization reaction of butynone 5
with phenyl hydrazine
Table 2 Synthesis of pyrazoles 3a–j via cyclocondensation of 5 and
hydrazines
Entry
Catalyst/load
Temperaturea [°C]
Yieldb [%]
Entry
Hydrazine R–
Pyrazole
Yielda
1
2
3
4
5
6
7
8
9
—
—
80
100
100
100
100
100
100
80
60
57
63
66
79
96
98
92c
99
1
2
3
4
5
H–
3a
3b
3c
3d
3e
91
85
76
85
82
Me–
t-Bu–
Ph–
H4SiW12O40/10 mol%
Amberlyst-15/50 mg
Nafion-H/50 mg
CF3COOH/10 mol%
CF3SO3H/10 mol%
K-10/50 mg
K-10/50 mg
100
6
7
3f
86
74
a Discover Benchmate microwave reactor, 10 min; reaction in
0.050 mmol scale for 5 and 0.075 mmol (1.5 equiv) of phenyl hydrazine
in the absence of solvent. b As determined by GC/MS. c Comparable
result was obtained using conventional heating at 100 °C for 10 min.
3g
8
9
3h
3i
73
75
Preliminary optimization experiments were carried out for the
cyclization reaction of phenyl/p-tolyl substituted butynone 5
(1 equiv, 0.05 mmol) and phenyl hydrazine (1.5 equiv, Table 1).
Since an elevated temperature is required, microwave heating
was applied to accelerate the reaction rate, moreover, the reaction
was carried out solvent-free. Even without a catalyst the reaction
proceeded, albeit with moderate yields and with formation of
other products (entries 1–2). Subsequently acidic catalysts were
screened, mostly heterogeneous, due to our interest in sustain-
able methods. The use of Keggin-type tungsten-based hetero-
polyacid catalyst or Amberlyst-15 acidic ion-exchange resin did
not procure improvements (entries 3–4) as compared to the non-
catalyzed reaction. More promising results were observed with
the use of Nafion-H, a fluoropolymer sulfonic acid (entry 5).18
The use of homogeneous catalysts, such as trifluoroacetic and
triflic acid, facilitated very good progress (entries 6–7); however,
the separation and recycling of the catalyst hampered the practi-
cality of this system.
Among the viable alternatives available for green synthetic
methods, clay-based catalysts have attracted attention due to their
versatile properties.19 These materials provide broad possibilities
for synthetic applications,20 particularly in the synthesis of het-
erocycles.21 The layered structure of these aluminosilicates
allows for the intercalation of different organic molecules, and
the ion-exchange capabilities procures the commutation of
specific metal ions. We turned our attention to montmorillonite
K-10, which has already been employed as a catalyst in the syn-
thesis of pyrazoles.22
10
3j
83
a [%], isolated yield; reactions were carried out in a microwave vial on a
0.250 mmol scale with 0.375 mmol of hydrazine and 250 mg of K-10
catalyst, at 100 °C in the absence of solvent; reaction time 10 min.
was developed, as illustrated in Table 2. The reactions were
carried out solvent-free using microwave heating. The products
were isolated using preparative TLC. Although we focused on
fluoroaryl-substituted pyrazoles due to potential biological
activity, hydrazines with alkyl (methyl and tert-butyl) as well as
benzoyl groups were also examined. The results of the reactions
of ketone 5 with various substituted hydrazines are provided in
Table 2. Although diminished nucleophilicity could be expected
for the benzoyl hydrazine, no detrimental effect on reactivity
was observed.
The structure of the new pyrazoles was confirmed by NMR
and MS. The characteristic NMR features for 3a–j include the
1H H-4 signals (6.14–6.51 ppm) and 13C C-4 and CH2 (benzyl)
signals (102.3–108.5/31.8–34.3 ppm). Mass spectra for 3 exhib-
ited intense molecular ions.
The molecular structure of a representative 1,3,5-trisubstituted
pyrazole and the regiochemistry of the method was confirmed by
X-ray crystallography.23 The molecule of expected 5-(4-methyl-
benzyl)-1H-pyrazole 3e is shown in Fig. 2.
The application of montmorillonite K-10 (entries 8–9) led to
the formation of the pyrazole 3a at 100 °C, with 99% yield, after
10 min, in the absence of solvent.
Since montmorillonite K-10 was found to be an effective cata-
lyst (Table 1), a preparative synthesis for a series of pyrazoles
We confirmed that the reaction is also applicable to 1-ethyl as
well as 4-cyclopropyl-substituted butynones, leading to 3-ethyl
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Acknowledgements
The NSF awards (CHE-0821487, CHE-0722547, and
CHE-1048719) are acknowledged. A.S is grateful for the Pro-
vost’s Graduate Student Research Award.
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