A convenient microwave-assisted propylphosphonic anhydride (T3P mediated one-pot pyrazolone synthesis

Article abstract of DOI:10.1002/ejoc.201300380

This paper describes a facile, efficient, and clean synthesis of various pyrazolones by employing T3P as a catalyst and performing the reaction under microwave irradiation. This two-step, one-pot reaction proceeded readily and tolerated a variety of functional groups. A wide range of pyrazolone derivatives were obtained in good to excellent yields. A one-pot, two-step procedure for the synthesis of pyrazolones is presented. This method, which uses T3P and microwave irradiation, is particularly easy to carry out and offers a notable alternative to the strongly acidic conditions that are generally employed with other synthetic approaches. Copyright

Full text of DOI:10.1002/ejoc.201300380

FULL PAPER
DOI: 10.1002/ejoc.201300380
A Convenient Microwave-Assisted Propylphosphonic Anhydride (T3P®)
Mediated One-Pot Pyrazolone Synthesis
Matthieu Desroses,*[a] Marie-Caroline Jacques-Cordonnier,[a] Sabin Llona-Minguez,[a]
Sylvain Jacques,[a] Tobias Koolmeister,[a] Thomas Helleday,[a] and Martin Scobie[a]
Keywords: Medicinal chemistry / Nitrogen heterocycles / Cyclization / Microwave chemistry / Phosphorus
This paper describes a facile, efficient, and clean synthesis
of various pyrazolones by employing T3P® as a catalyst and
performing the reaction under microwave irradiation. This
two-step, one-pot reaction proceeded readily and tolerated
a variety of functional groups. A wide range of pyrazolone
derivatives were obtained in good to excellent yields.
useful for managing many oxidative stress-related dis-
eases.[9]
Introduction
Propylphosphonic anhydride (T3P®) has been commonly
used as a water scavenger and coupling reagent for the syn-
thesis of amides.[1] Because of its properties, which include
a broad functional group tolerance, low toxicity, and easy
workup procedures, new applications have recently been de-
veloped for this reagent.[2] For instance, T3P® has been used
in dehydration chemistry that involves the conversion of
carboxylic acids and amides into nitriles as well as in the
synthesis of alkenes, isonitriles, and several substituted het-
erocycles.[3] More recently, T3P® was used as an efficient
catalyst for the acetalization or thioacetalization of alde-
hydes, for the reduction of carboxylic acids into alcohols,
and for the synthesis of 4-thiazolidinones and 5,6-dihy-
drophenanthridine derivatives.[4]
During the last decade, compounds that contain a pyr-
azolone moiety, or its related analogues, have received con-
siderable attention in medicinal chemistry. These com-
pounds exhibit antitubercular,[5] antifungal,[6] anti-infec-
tious,[8] anticancer,[10] antipyretic and analgesic,[11] antioxi-
dant,[12] and antimicrobial properties.[13] Finally, some of
the pyrazolone derivatives have been developed to treat a
variety of disorders that are caused by human immuno-
deficiency virus (HIV)[14] and hereditary hemochrom-
atosis.[15]
Results and Discussion
Initially, a model reaction was conducted by treating
ethyl benzoylacetate (1a, 0.5 mmol) with phenylhydrazine
(2a, 0.5 mmol) in the presence of an excess amount of T3P®
(50% solution in EtOAc, 4 equiv.) at 100 °C under micro-
wave irradiation (MW) for 15 min (see Table 1, Entry 1).
We were pleased to find that T3P® did mediate this cycliza-
tion. The reaction conditions were then optimized by fine-
tuning the equivalents of T3P®, the reaction time, and the
temperature.
In continuation of our work on the development of use-
ful synthetic methodologies,[3a] we reasoned that T3P®
could be employed for the construction of the pyrazolone
ring. Pyrazolones are traditionally synthesized by treatment
of a β-keto ester with hydrazine under acidic conditions at
high temperature for a long reaction time.[5–8] Conse-
quently, new, mild, and expedient protocols for these deriv-
atives are of significant importance. The pyrazolone ring is
an important scaffold that is found in pharmaceuticals that
exhibit widespread pharmacological properties. One of the
most relevant examples, edaravone (3-methyl-1-phenyl-2-
pyrazolin-5-one, Radicut®, Mitsubishi Tanabe Pharma
Corporation) is used to treat patients in the acute stages
of cerebral thrombosis or embolism and stroke. Moreover,
because of its antioxidant properties, edaravone might be
Decreasing the amount of T3P® from 4 to 2 equiv. did
not affect the outcome of the reaction, which indicated that
it was sufficient to have 2 equiv. of T3P® (see Table 1, En-
try 2). We then decided to evaluate the impact of changing
the reaction time, and a series of experiments were carried
out for periods of 10 and 5 min (see Table 1, Entries 3 and
4). Using T3P® (2 equiv.), the reaction of 1a and 2a in
EtOAc at 100 °C for only 5 min proved to be optimal for
this cyclodehydration, and the isolated yield from this con-
version was excellent (90%, see Table 2, Entry 1). Further-
more, decreasing the amount of T3P® from 2 equiv. to
1.5 equiv. or the reaction temperature to 90 °C lowered the
conversion yield (see Table 1, Entries 5 and 6, respectively).
[a] Science for Life Laboratory, Unit of Translational Medicine
and Chemical Biology, Department of Medical Biochemistry
and Biophysics, Karolinska Institute,
171 21 Stockholm, Sweden
E-mail: matthieu.desroses@scilifelab.se
Homepage: http://helleday.org/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300380.
Eur. J. Org. Chem. 2013, 5879–5885
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5879

M. Desroses et al.
FULL PAPER
Table 1. Optimization of reaction conditions.
of the reaction. Several aliphatic β-keto esters were also
suitable substrates for the reaction (i.e., 1l–1q, see Table 2,
Entries 12–17). In these cases, steric effects appear to influ-
ence the rate and yield of the reaction. Indeed, when ethyl
pivaloylacetate (1n) and phenylhydrazine (2a) were used as
substrates, the synthesis of 3-tert-butyl-1-phenyl-1H-pyr-
azol-5(4H)-one (3n) required a higher temperature and
longer reaction time (e.g., 120 °C and 10 min). Further-
more, this methodology was employed to synthesize edara-
vone (3-methyl-1-phenyl-2-pyrazolin-5-one, 3l), in a good
yield of 83% (see Table 2, Entry 12).
Notably, the use of ethyl 2-cyanoacetoacetate (1r) led to
the formation of 3ra instead of expected pyrazolone 3r (see
Table 2, Entry 18). Under similar conditions, aminopyr-
azoles were obtained by condensation of keto esters with
hydrazine derivatives.[16] This presumably proceeds as de-
picted in Scheme 1.
Entry T3P® [equiv.]
Time [min] T [°C] % Conversion[a]
1
2
4
2
15
15
10
5
100
100
100
100
100
90
100
100
99
98
77
87
14
87
89
86
3
4
2
2
5
6
1.5
2
5
5
5
5
5
7
0
100
100
100
100
8[b]
9[c]
10
1.5 + AcOH
1.5 + AcOH
0 + AcOH
5
[a] Determined by LC–MS analysis (for details, see Exp. Sect.).
[b] Reaction conducted in EtOAc. [c] Reaction conducted in EtOH.
Finally, to validate that the ring-closing dehydration was
mediated by T3P® and not by a thermal process only, a
control experiment was conducted. As expected, heating the
mixture of 1a and 2a at 100 °C in EtOAc without T3P® for
5 min under microwave irradiation gave only 14% conver-
sion (see Table 1, Entry 7). With the goal to decrease the
amount of required T3P®, we carried out the reaction with
1.5 equiv. of T3P® and two drops of acetic acid in either
EtOAc or EtOH (see Table 1, Entries 8 and 9). No signifi-
cant difference was observed when the reaction was carried
out in either of these two solvents (87% conversion in
EtOAc, 89% in EtOH). These conversions were similar to
that obtained by using only two drops of acetic acid with-
out T3P® (e.g., 86%, see Table 1, Entry 10). Thus, under
our reaction conditions, no synergistic effect was obtained
by combining T3P® and acetic acid. The probable degrada-
tion of T3P® in acidic media to produce phosphoric acid
could explain this result.
Scheme 1. Plausible mechanism of formation of 3ra.
The first step of this mechanism is the condensation of
hydrazine 2a with ethyl 2-cyanoacetoacetate 1r (a Knoeven-
The optimized conditions [e.g., T3P® (2 equiv.), MW, agel-type condensation) to produce intermediate 4. This
5 min at 100 °C] were then used to explore the scope of this condensation could be assisted by the presence of T3P®.
reaction. The results in Table 2 show that a variety of β- Subsequently, 4 could undergo an intramolecular cycliza-
keto esters that contain electron-donating (see Table 2, En- tion, which upon tautomerization would lead to 3ra. In this
tries 2–5), electron-withdrawing (see Table 2, Entries 8–11), plausible mechanism, only 1 equiv. of T3P® is needed. To
heteroaromatic, and aliphatic groups (see Table 2, Entries 6 confirm this hypothesis, two reactions were conducted, that
and 7 as well as 12–17, respectively) were successfully em- is, one with only 1 equiv. of T3P® and one without T3P®.
ployed to prepare the corresponding pyrazolone derivatives These reactions were monitored by LC–MS analysis. To our
in good to excellent yields. We were pleased to see that the pleasure, no product was formed when the reactants were
reaction worked well with electron-donating and electron- irradiated under microwave conditions at 100 °C for 5 min
withdrawing substituents as well as heteroaromatic β-keto in EtOAc in the absence of T3P®. With only 1 equiv. of
esters (see Table 2, Entries 2–11). Only ethyl (3-chlorobenz- T3P®, a conversion yield of 81% was obtained after 15 min
oyl)acetate (1k, see Table 2, Entry 11) led to a small de- of reaction time. More experiments with regard to the use
crease in the yield to 75%, which indicated the limited in- of T3P® in Knoevenagel-type condensations are under in-
fluence of an electron-withdrawing substituent on the yield vestigation and will be reported soon.
5880
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5879–5885

One-Pot Pyrazolone Synthesis
Table 2. Pyrazolone synthesis in the presence of T3P®: scope of β-keto esters.
[a] Reactions conducted on a 0.5 mmol scale, isolated yield. [b] Reaction conducted on a 5 mmol scale, isolated yield.
The substrate scope of the reaction was further extended with the electron-withdrawing trifluoromethyl group (see
to various substituted hydrazines. Thus, ethyl benzoylacet- Table 3, Entry 3) did not require any adjustment to the re-
ate 1a was treated with a range of hydrazines under our action conditions, whereas para-methoxyphenylhydrazine
optimized reaction conditions (see Table 3). To our delight, needed a longer reaction time (2ϫ 5 min) and a higher tem-
hydrazines that contain either electron-donating (see perature (120 °C) to achieve full conversion (see Table 3,
Table 3, Entries 1 and 2) or electron-withdrawing groups Entry 2). Other para substitutents (i.e., 4-methyl and 4-
(see Table 3, Entries 3–6) were well tolerated to afford the fluoro) furnished the expected derivatives by following the
corresponding pyrazolones in good yields. Surprisingly, the previously optimized conditions (see Table 3, Entries 1 and
substitution of the phenylhydrazine at the para position 4). Furthermore, ortho- and meta-substituted hydrazines
Eur. J. Org. Chem. 2013, 5879–5885
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5881

M. Desroses et al.
FULL PAPER
Table 3. Pyrazolone synthesis in the presence of T3P®: scope of cedure to construct pyrazolone analogues. With this simple
substituted hydrazines.
and rapid method, a series of compounds were synthesized
to examine the extension and limitations of this methodol-
ogy. This approach offers a notable alternative to the
strongly acidic conditions that are generally applied with
other synthetic methods and, therefore, may have applica-
tion to the syntheses of biological and pharmaceutical mo-
lecules that contain a pyrazolone scaffold. During this
study, we also identified the potential use of T3P® in Knoe-
venagel-type condensations. Further studies with regard to
this new employment of T3P® are currently under investiga-
tion and will be reported soon.
Experimental Section
General Methods: All the reagents were commercially available and
used without further purification. Analytical thin layer chromatog-
raphy was performed on silica gel 60 F-254 plates (E. Merck) and
visualized by using UV light. Flash column chromatography was
performed with Merck silica gel 60 (40–63 mm). The 1H NMR
spectroscopic data were recorded at 400 MHz, and the 13C NMR
spectroscopic data were recorded at 100 MHz. The chemical shifts
for the 1H and 13C NMR are referenced to the residual solvent
signals [1H NMR: CDCl3 at δ = 7.26 ppm, CD3OD at δ =
3.31 ppm, deuterated dimethyl sulfoxide ([D6]DMSO) at δ =
2.50 ppm; 13C NMR: CDCl3 at δ = 77.16 ppm, CD3OD at δ =
49.01 ppm, and [D6]DMSO at δ = 39.52 ppm]. The microwave reac-
tions were performed in a Biotage Initiator that produced a con-
trolled irradiation at 2450 MHz with a power of 0–300 W. The reac-
tion temperature was determined by using a built-in online IR sen-
sor. All reactions were performed in sealed microwave-transparent
process vials that were designed for reaction volumes of 0.5–2 mL.
Analytical LC–MS data were recorded with an Agilent MSD mass
spectrometer that was connected to an Agilent 1100 system with:
(i) System A: Column ACE 3 C8 (50ϫ3.0 mm), H2O [+ 0.1% tri-
fluoroacetic acid (TFA)] and MeCN as mobile phases, flow rate:
1 mL/min, and a gradient time of 3.0 min or (ii) System B: Column
Xterra MSC18 (50ϫ3.0 mm), H2O [containing NH4HCO3 (10 mm
solution), pH = 10] and MeCN as mobile phases, flow rate: 1 mL/
min, and a gradient time of 3.0 min. Preparative HPLC analyses
were performed with a Gilson HPLC System with Column Xbridge
Prep C18, 5 μm CBD (30ϫ75 mm), H2O [containing NH4HCO3
(50 mm solution), pH = 10] and MeCN as mobile phases, flow rate:
45 mL/min, and a gradient time of 9 min. UV (254 or 214 nm) and
MS (ESI+) detection were used for both the LC–MS and prepara-
tive HPLC analyses. The percent conversion in Table 1 was esti-
mated by comparing the peak area of 3a to the combined peak
area(s) of 1a and/or 2a. Compounds 3a,[17] 3h,[18] 3l,[17] 3n,[19] 3q,[20]
3ra,[16] 3t,[17] and 3v[21] are known compounds, and the spectro-
scopic data that were obtained are in agreement with the proposed
structures and match those reported. Compounds 3b,[22] 3c,[18]
[a] Reactions conducted on a 0.5 mmol scale, isolated yield.
3d,[23] 3e,[24] 3f,[25] 3g,[26] 3j,[27] 3k,[28] 3m,[29] 3o,[30] 3p,[31] and 3s[32]
are known compounds, but their complete NMR spectroscopic
data have not been previously reported. Melting points were ob-
tained with a Stuart Scientific SMP3 apparatus. It is well-known
also performed well (see Table 3, Entries 5 and 6), which
indicated the limited influence of steric factors on the reac-
tion outcome.
that the pyrazolone ring exists in various prototropic tautomeric
forms. From the 1H and 13C NMR chemical shifts, we assume that
the keto form predominates in low polarity solvent such as CDCl3,
whereas the enol form predominates in the [D6]DMSO and
Conclusions
In summary, we have developed a new, efficient, and
CD3OD solutions. Furthermore, this is in agreement with literature
easily reproducible T3P® mediated microwave-assisted pro- data.[33]
5882
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5879–5885

One-Pot Pyrazolone Synthesis
General Experimental Procedure for Compounds 3a–3j: T3P® (50%
in EtOAc, 1 mmol, 2 equiv.) was added to a mixture of the β-keto
ester (0.5 mmol) and hydrazine (0.5 mmol) in a microwave vial. The
reaction volume was then adjusted to 0.5 mL with EtOAc, and the
vessel was sealed under air. The mixture was then heated under
microwave irradiation at 100 °C for 5 min. The residue was sus-
pended in water, and CH2Cl2 was then added. The organic layer
was washed with a saturated solution of NaHCO3. The aqueous
layers were combined and extracted with CH2Cl2. The combined
organic layers were then washed with brine and dried with Na2SO4.
Evaporation of the solvent afforded the required product in suf-
ficient purity.
1H NMR (400 MHz, CDCl3): δ = 7.94 (dd, J = 7.5, 1.2 Hz, 2 H),
7.75 (s, 1 H), 7.51 (t, J = 1.5 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 2 H),
7.23 (t, J = 7.5 Hz, 1 H), 6.87 (d, J = 1.5 Hz, 1 H), 3.73 (s, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.4, 148.8, 144.4,
142.6, 137.9, 128.8, 125.2, 116.4, 119.1, 107.3, 40.1 ppm. LC–MS:
m/z = 227 [M + H]+.
3-(4-Nitrophenyl)-1-phenyl-1H-pyrazol-5(4H)-ol (3h): Yellow pow-
der (140 mg, quantitative yield), m.p. 187–188 °C (EtOH); ref.[18]
1
m.p. 190–191 °C. H NMR (400 MHz, [D6]DMSO): δ = 12.02 (br.
s, 1 H), 8.28 (d, J = 9.1 Hz, 2 H), 8.11 (d, J = 9.1 Hz, 2 H), 7.84
(dd, J = 7.6, 1.1 Hz, 2 H), 7.53 (t, J = 7.6 Hz, 2 H), 7.35 (tt, J =
7.6, 1.1 Hz, 1 H), 6.21 (s, 1 H) ppm. LC–MS: m/z = 282 [M +
H]+.
1,3-Diphenyl-1H-pyrazol-5(4H)-one (3a): Yellow-orange solid
(107 mg, 90% yield), m.p. 138–140 °C (EtOH); ref.[17] m.p. 136–
138 °C. 1H NMR (400 MHz, CDCl3): δ = 7.99 (dd, J = 7.6, 1.0 Hz,
2 H), 7.79–7.77 (m, 2 H), 7.48–7.42 (m, 5 H), 7.25 (t, J = 7.6 Hz,
1 H), 3.86 (s, 2 H) ppm. LC–MS: m/z = 237 [M + H]+.
1-Phenyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5(4H)-one (3i):
Yellow powder (144 mg, 95% yield); m.p. 164–166 °C (diisopropyl
ether). 1H NMR (400 MHz, CDCl3): δ = 7.97 (dd, J = 7.5, 1.1 Hz,
2 H), 7.90 (d, J = 8.0 Hz, 2 H), 7.73 (d, J = 8.0 Hz, 2 H), 7.47 (t,
J = 7.5 Hz, 2 H), 7.27–7.23 (m, 1 H), 3.87 (s, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.1, 153.3, 138.1, 134.3, 129.1, 126.4,
126.3, 126.2, 126.1, 125.9, 119.4, 39.7 ppm. LC–MS: m/z = 305 [M
+ H]+.
3-(4-Methylphenyl)-1-phenyl-1H-pyrazol-5(4H)-one (3b): Yellow so-
lid (112 mg, 89% yield), m.p. 154–156 °C (EtOH); ref.[22] m.p.
154 °C. 1H NMR (400 MHz, CDCl3): δ = 7.99 (dd, J = 7.5, 1.0 Hz,
2 H), 7.67 (d, J = 8.1 Hz, 2 H), 7.45 (t, J = 7.5 Hz, 2 H), 7.27 (d,
J = 8.1 Hz, 2 H), 7.23 (t, J = 7.5 Hz, 1 H), 3.82 (s, 2 H), 2.41 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.2, 154.7, 141.1,
138.1, 129.6, 128.8, 128.1, 125.9, 125.2, 119.0, 39.7, 21.5 ppm. LC–
MS: m/z = 251 [M + H]+.
3-(2-Chlorophenyl)-1-phenyl-1H-pyrazol-5(4H)-one (3j): Yellow so-
lid (130 mg, 96% yield); m.p. 139–141 °C (diisopropyl ether). 1H
NMR (400 MHz, CDCl3): δ = 8.00–7.95 (m, 3 H), 7.48–7.42 (m, 3
H), 7.41–7.35 (m, 2 H), 7.25 (tt, J = 7.5, 1.1 Hz, 1 H), 4.14 (s, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.5, 153.5, 138.0,
132.7, 131.3, 131.0, 129.9, 129.8, 128.9 (2 C), 127.2, 125.5, 119.1 (2
C), 43.2 ppm. LC–MS: m/z = 271 [M + H]+, 273.
3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazol-5(4H)-one (3c): Red-
orange solid (131 mg, 98% yield), m.p. 134–136 °C (EtOH); ref.[18]
1
m.p. 133 °C. H NMR (400 MHz, CDCl3): δ = 7.98 (dd, J = 7.8,
1.0 Hz, 2 H), 7.72 (d, J = 8.9 Hz, 2 H), 7.44–7.40 (m, 2 H), 7.23–
7.20 (m, 1 H), 6.97 (d, J = 8.9 Hz, 2 H), 3.86 (s, 3 H), 3.80 (s, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.2, 161.6, 154.4,
138.2, 128.8, 127.6, 125.1, 123.6, 121.3, 119.0, 114.3, 113.5, 55.4,
39.7 ppm. LC–MS: m/z = 267 [M + H]+.
General Experimental Procedure for Compounds 3k–3p, 3t, and 3u:
T3P® (50% in EtOAc, 1 mmol, 2 equiv.) was added to a mixture
of the β-keto ester (0.5 mmol) and hydrazine (0.5 mmol) in a micro-
wave vial. The reaction volume was then adjusted to 0.5 mL with
EtOAc, and the vessel was sealed under air. The mixture was then
heated under microwave irradiation for the time and temperature
that are indicated in Table 2. The solvent was removed under re-
duced pressure, and the residue was purified by filtration through
a plug of silica gel.
3-(3-Methoxyphenyl)-1-phenyl-1H-pyrazol-5(4H)-one (3d): Orange
solid (129 mg, 97% yield), m.p. 124–125 °C (EtOH); ref.[23] m.p.
137–138 °C. 1H NMR (400 MHz, CDCl3): δ = 7.98 (dd, J = 7.6,
1.3 Hz, 2 H), 7.45–7.41 (m, 2 H), 7.37–7.35 (m, 2 H), 7.30 (dt, J =
8.1, 1.1 Hz, 1 H), 7.25–7.20 (m, 1 H), 7.02 (ddd, J = 8.1, 2.6, and
1.0 Hz, 1 H), 3.88 (s, 3 H), 3.83 (s, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.2, 160.0, 154.5, 138.1, 132.2, 130.0, 128.9, 125.4,
119.1, 118.7, 116.7, 110.8, 55.4, 39.8 ppm. LC–MS: m/z = 267 [M
+ H]+.
3-(3-Chlorophenyl)-1-phenyl-1H-pyrazol-5(4H)-one (3k): Purifica-
tion by filtration through silica gel (gradient 5–30% EtOAc in hex-
1
anes) afforded 3k (102 mg, 75% yield) as a light yellow foam. H
NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 7.8 Hz, 2 H), 7.77 (t, J
= 1.6 Hz, 1 H), 7.59 (dt, J = 7.3, 1.6 Hz, 1 H), 7.46–7.36 (m, 4 H),
7.25–7.19 (m, 1 H), 3.79 (s, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.1, 153.4, 138.1, 135.2, 132.7, 130.7, 130.3, 129.0,
126.0, 125.6, 124.2, 119.2, 39.6 ppm. LC–MS: m/z = 271 [M +
H]+, 273.
3-(2-Methoxyphenyl)-1-phenyl-1H-pyrazol-5(4H)-one (3e): Orange
solid (132 mg, 99% yield), m.p. 133–134 °C (EtOH); ref.[24] m.p.
133–134 °C. 1H NMR (400 MHz, CDCl3): δ = 8.09 (dd, J = 7.8,
1.8 Hz, 1 H), 8.01 (dd, J = 7.6, 1.0 Hz, 2 H), 7.45–7.40 (m, 3 H),
7.23–7.19 (m, 1 H), 7.07 (td, J = 7.6, 1.0 Hz, 1 H), 6.98 (d, J =
7.6 Hz, 1 H), 4.03 (s, 2 H), 3.89 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 171.7, 158.2, 154.1, 138.7, 132.3, 129.2 (2 C), 128.3,
125.5, 121.4, 120.4, 119.4 (2 C), 111.9, 55.8, 44.3 ppm. LC–MS:
m/z = 267 [M + H]+.
3-Methyl-1-phenyl-1H-pyrazol-5(4H)-one (3l): Purification by fil-
tration through silica gel (gradient 5–40% EtOAc in hexanes) af-
forded 3l (72 mg, 83% yield) as a white powder, m.p. 120–122 °C
(EtOH); ref.[17] m.p. 127–129 °C. 1H NMR (400 MHz, CDCl3): δ
= 7.89–7.81 (m, 2 H), 7.42–7.35 (m, 2 H), 7.21–7.14 (m, 1 H), 3.43
(s, 2 H), 2.19 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
170.7, 156.5, 138.1, 128.9 (2 C), 125.2, 119.0 (2 C), 43.2, 17.1 ppm.
LC–MS: m/z = [M + H]+ 175.
2-Phenyl-5-pyridin-2-yl-1,2-dihydro-pyrazol-3-one (3f): Light brown
solid (99 mg, 83% yield), m.p. 179–181 °C (EtOH); ref.[25] m.p.
178–179 °C. 1H NMR (400 MHz, CDCl3): δ = 8.64 (d, J = 4.8 Hz,
1 H), 8.15 (d, J = 7.8 Hz, 1 H), 7.98 (d, J = 7.6 Hz, 2 H), 7.81 (td,
J = 7.8, 1.7 Hz, 1 H), 7.46 (t, J = 7.6 Hz, 2 H), 7.36–7.32 (m, 1 H),
7.25 (t, J = 7.6 Hz, 1 H), 4.02 (s, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.9, 155.9, 149.9, 149.5, 138.0, 138.5, 138.0, 136.5,
128.8, 125.4, 124.6, 120.2, 119.1, 39.7 ppm. LC–MS: m/z = 238 [M
+ H]+.
3-Ethyl-1-phenyl-1H-pyrazol-5(4H)-one (3m): Purification by fil-
tration through silica gel (gradient 5–30% EtOAc in hexanes) af-
forded 3m (86 mg, 91% yield) as a light yellow solid; m.p. 99–
1
101 °C (EtOH). H NMR (400 MHz, CDCl3): δ = 7.91–7.82 (m, 2
3-(Furan-3-yl)-1-phenyl-1H-pyrazol-5(4H)-one (3g): Purple solid
H), 7.43–7.33 (m, 2 H), 7.21–7.12 (m, 1 H), 3.41 (s, 2 H), 2.52 (q, J
(111 mg, 98% yield), m.p. 140–141 °C (EtOH); ref.[26] m.p. 182 °C. = 7.5 Hz, 2 H), 1.25 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (100 MHz,
Eur. J. Org. Chem. 2013, 5879–5885
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5883

M. Desroses et al.
FULL PAPER
CDCl3): δ = 170.7, 160.9, 138.2, 128.9 (2 C), 125.1, 118.9 (2 C), 125.2, 118.7 (2 C), 22.3, 12.6 ppm. LC–MS: m/z = 189 [M + H]+.
41.6, 24.7, 10.8 ppm. LC–MS: m/z = 189 [M + H]+.
General Experimental Procedure for Compounds 3s and 3v–3x:
3-tert-Butyl-1-phenyl-1H-pyrazol-5(4H)-one (3n): Purification by
filtration through silica gel (gradient 5–15% EtOAc in hexanes)
T3P® (50% in EtOAc, 1 mmol, 2 equiv.) was added to a mixture
of the β-keto ester (0.5 mmol) and hydrazine (0.5 mmol) in a micro-
wave vial. The reaction volume was then adjusted to 0.5 mL with
EtOAc, and the vessel was sealed under air. The mixture was then
heated at 100 °C for 5 min under microwave irradiation. The resi-
due was suspended in water, and then CH2Cl2 was added. The or-
ganic layer was washed with a saturated solution of NaHCO3. The
aqueous layers were combined and extracted with CH2Cl2. The
afforded 3n (78 mg, 72% yield) as a white powder, m.p. 112–113 °C
(EtOH); ref.[19] m.p. 117–119 °C. 1H NMR (400 MHz, CDCl3): δ
= 7.93–7.86 (m, 2 H), 7.41–7.34 (m, 2 H), 7.19–7.12 (m, 1 H), 3.44
(s, 2 H), 1.27 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
170.9, 166.6, 138.4, 128.8, 124.9, 118.9, 39.0, 35.0, 28.2 ppm. LC–
MS: m/z = 217 [M + H]+.
combined organic layers were then washed with brine and dried
with Na2SO4. After evaporation of the solvent, the obtained resi-
due was purified by flash chromatography on silica gel (pentane/
EtOAc, 4:1).
3-Cyclopropyl-1-phenyl-1H-pyrazol-5(4H)-one (3o): Purification by
filtration through silica gel (gradient 5–30% EtOAc in hexanes)
afforded 3o (92 mg, 92% yield) as a light yellow solid; m.p. 114–
1
115 °C (EtOH). H NMR (400 MHz, CDCl3): δ = 7.88–7.83 (m, 2
H), 7.41–7.35 (m, 2 H), 7.20–7.14 (m, 1 H), 3.31 (s, 2 H), 1.87 (tt,
J = 8.3, 5.0 Hz, 1 H), 1.06–1.00 (m, 2 H), 0.91–0.86 (m, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 170.1, 161.6, 138.1, 128.8 (2 C),
125.0, 118.9 (2 C), 40.1, 12.2, 7.9 (2 C) ppm. LC–MS: m/z = 201
[M + H]+.
3-Phenyl-1-(4-methylphenyl)-pyrazol-5(4H)-ol (3s): White powder
(95 mg, 76% yield). 1H NMR (400 MHz, [D6]DMSO): δ = 7.81
(dd, J = 7.0, 1.3 Hz, 2 H), 7.72 (d, J = 8.6 Hz, 2 H), 7.42–7.38 (m,
2 H), 7.33–7.29 (m, 1 H), 7.28 (dd, J = 8.6, 0.5 Hz, 2 H), 5.99–5.91
(br. s, 1 H), 2.34 (s, 3 H) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 154.3, 149.2, 137.2, 136.6, 134.6, 133.5, 129.2, 128.5, 127.7,
125.0, 120.9, 20.51 ppm. LC–MS: m/z = 251 [M + H]+.
2-Phenyl-4,5,6,7-tetrahydro-2H-indazol-3-ol (3p): Purification by
filtration through silica gel (pentane/EtOAc, 5:1) afforded 3p
(94 mg, 88% yield) as a yellow solid. 1H NMR (400 MHz,
CD3OD): δ = 7.65–7.61 (m, 2 H), 7.53–7.48 (m, 2 H), 7.38–7.34
(m, 1 H), 2.63 (t, J = 6.0 Hz, 2 H), 2.39 (t, J = 6.0 Hz, 2 H),
1.90–1.78 (m, 4 H) ppm. 13C NMR (100 MHz, CD3OD): δ = 151.0,
149.8, 137.0, 130.4 (2 C), 128.3, 123.0 (2 C), 104.5, 23.4, 22.9, 22.7,
19.6 ppm. LC–MS: m/z = [M + H]+ 215.
3-Phenyl-1-(4-fluorophenyl)-pyrazol-5(4H)-one (3v): White solid
(93 mg, 73% yield), m.p. 147–149 °C (diisopropyl ether); ref.[21]
1
m.p. 149–153 °C. H NMR (400 MHz, CDCl3): δ = 7.98–7.93 (m,
2 H), 7.79–7.76 (m, 2 H), 7.48–7.46 (m, 3 H), 7.14–7.09 (m, 2 H),
3.86 (s, 2 H) ppm. LC–MS: m/z = 255 [M + H]+.
3-Phenyl-1-(4-methoxyphenyl)-pyrazol-5(4H)-one (3t): Purification
by filtration through silica gel (pentane/EtOAc, 5:1) afforded 3t
(103 mg, 77% yield) as an off-white solid. 1H NMR (400 MHz,
CDCl3): δ = 7.86 (d, J = 9.0 Hz, 2 H), 7.78–7.74 (m, 2 H), 7.48–
7.42 (m, 3 H), 6.97 (d, J = 9.0 Hz, 2 H), 3.83 (s, 3 H), 3.82 (s, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.9, 157.2, 154.5,
131.4, 130.9, 130.6, 128.9 (2 C), 125.9 (2 C), 121.0 (2 C), 114.0 (2
C), 55.4, 39.4 ppm. LC–MS: m/z = [M + H]+ 267.
3-Phenyl-1-(2-bromophenyl)pyrazol-5(4H)-one (3w): Light brown
solid (125 mg, 79% yield); m.p. 162–164 °C (diisopropyl ether). 1H
NMR (400 MHz, [D6]DMSO): δ = 7.81 (d, J = 8.3 Hz, 1 H), 7.76
(d, J = 7.3 Hz, 2 H), 7.55–7.50 (m, 2 H), 7.45–7.36 (m, 3 H), 7.31–
7.28 (m, 1 H), 5.90 (br. s, 1 H) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 154.3, 149.9, 137.5, 133.7, 133.1, 130.6, 130.2, 128.5
(2 C), 128.4, 127.6, 124.9 (2 C), 121.6, 83.3 ppm. LC–MS: m/z =
315 [M + H]+, 317.
3-Phenyl-1-(4-trifluorophenyl)-pyrazol-5(4H)-one (3u): Purification
by filtration through silica gel (pentane/EtOAc, 5:1) afforded 3u
(120 mg, 79% yield) as a white solid; m.p. 149–150 °C (diisopropyl
ether). 1H NMR (400 MHz, CDCl3): δ = 8.17 (d, J = 8.6 Hz, 2 H),
7.80–7.77 (m, 2 H), 7.69 (d, J = 8.6 Hz, 2 H), 7.49–7.47 (m, 3 H),
3.88 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.6, 155.0,
141.0, 129.2, 127.4, 126.5 (2 C), 126.3 (q, J = 32.6 Hz), 125.6 (q, J
= 3.8 Hz, 2 C), 122.9 (2 C), 120.2 (q, J = 269.9 Hz), 118.5 (2 C),
39.9 ppm. LC–MS: m/z = 305 [M + H]+.
3-Phenyl-1-(3-bromophenyl)pyrazol-5(4H)-one (3x): Light brown
powder (132 mg, 84% yield); m.p. 111–113 °C (diisopropyl ether).
1H NMR (400 MHz, [D6]DMSO): δ = 12.13 (br. s, 1 H), 8.04 (s, 1
H), 7.90–7.83 (m, 3 H), 7.46–7.33 (m, 5 H), 6.03 (s, 1 H) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 154.4, 150.3, 140.2, 133.0,
131.0, 128.6 (2 C), 128.2 (2 C), 125.3 (2 C), 122.9, 121.7, 119.4,
85.6 ppm. LC–MS: m/z = 315 [M + H]+, 317.
Ethyl 5-Amino-3-methyl-1-phenyl-1H-pyrazole-4-carboxylate (3ra):
T3P® (50% in EtOAc, 1 mmol, 2 equiv.) was added to a mixture
of ethyl 2-cyanoacetoacetate (1r, 0.5 mmol) and phenylhydrazine
(2a, 0.5 mmol) in a microwave vial. The reaction volume was then
adjusted to 0.5 mL with EtOAc, and the vessel was sealed under
air. The mixture was then heated under microwave irradiation at
100 °C for 5 min. The solvent was removed under reduced pressure,
and the residue was purified by preparative HPLC (XBridge C18,
MeCN/NH4CO3, gradient 25–95% MeCN) to afford 3ra (52 mg,
5-Hydroxy-3,4-dimethyl-1-phenylpyrazole (3q): T3P® (50% in
EtOAc, 1 mmol, 2 equiv.) was added to a mixture of ethyl 2-methyl-
acetoacetate (1q, 0.5 mmol) and phenylhydrazine (2a, 0.5 mmol) in
a microwave vial. The reaction volume was then adjusted to 0.5 mL
with EtOAc, and the vessel was sealed under air. The mixture was
then heated under microwave irradiation at 100 °C for 5 min. The
residue was suspended in water, and then CH2Cl2 was added. The
organic layer was washed with a saturated solution of NaHCO3.
The aqueous layers were combined and extracted with CH2Cl2. The
combined organic layers were then washed with brine and dried
with Na2SO4. After evaporation of the solvent, the obtained resi-
due was purified by flash chromatography on silica gel (hexane/
EtOAc, 1:1 and then 100% ethyl acetate) to afford 3q (82 mg, 87%
1
42% yield) as a buff-colored solid. H NMR (400 MHz, CDCl3): δ
= 7.52–7.46 (m, 4 H), 7.38–7.34 (m, 1 H), 5.33 (br. s, 2 H), 4.33 (q,
J = 7.2 Hz, 2 H), 2.40 (s, 3 H), 1.38 (t, J = 7.2 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 165.2, 150.2, 149.9, 137.5, 129.6,
127.8, 123.8, 94.6, 59.4, 14.5 ppm. LC–MS: m/z = 246 [M + H]+.
1
yield) as a colorless solid. H NMR (400 MHz, CDCl3): δ = 7.88
(dd, J = 7.4, 1.3 Hz, 2 H), 7.42–7.37 (m, 2 H), 7.21 (tt, J = 7.4, Supporting Information (see footnote on the first page of this arti-
1.3 Hz, 1 H), 3.27 (br. s, 1 H), 2.19 (s, 3 H), 1.53 (s, 3 H) ppm. 13
NMR (100 MHz, CDCl3): δ = 173.9, 162.4, 137.6, 128.8 (2 C),
C
cle): General experimental procedure and 1H and 13C spectra of
compounds.
5884
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5879–5885

One-Pot Pyrazolone Synthesis
[11] a) S. A. M. El-Hawash, E. S. A. M. Badawey, I. M. El-Ash-
mawey, Eur. J. Med. Chem. 2006, 41, 155; b) N. Uramaru, H.
Shigematsu, A. Toda, R. Eyanagi, S. Kitamura, S. Ohta, J.
Med. Chem. 2010, 53, 8727.
[12] K. Chegaev, C. Cena, M. Giorgis, B. Rolando, P. Tosco, M.
Bertinaria, R. Fruttero, P. A. Carrupt, A. Gasco, J. Med.
Chem. 2009, 52, 574.
Acknowledgments
Technical support from The Laboratories for Chemical Biology at
Karolinska Institutet (LCBKI) (http://www.cbcs.se/lcbki/) and
ChemAxon (http://www.chemaxon.com) is gratefully acknowl-
edged.
[13] a) R. Venkat Ragavan, V. Vijayakumar, N. Suchetha Kumari,
Eur. J. Med. Chem. 2009, 44, 3852; b) S. Bondock, R. Rabie,
H. A. Etman, A. A. Fadda, Eur. J. Med. Chem. 2008, 43, 2122.
[14] O. Barba, L. H. Jones, WO Patent 029042 A1, 2004.
[15] J. A. Cadieux, Z. Zhang, M. Mattice, A. Brownlie-Cutts, J. Fu,
L. G. Ratkay, R. Kwan, J. Thompson, J. Sanghara, J. Zhong,
Y. P. Goldberg, Bioorg. Med. Chem. Lett. 2012, 22, 90.
[16] J.-F. Li, Y.-Q. Zhu, X. Wang, H.-Z. Yang, J. Heterocycl. Chem.
2007, 44, 749.
[17] Y.-Y. Huang, H.-C. Lin, K.-M. Cheng, W.-N. Su, K.-C. Sung,
T.-P. Lin, J.-J. Huang, S.-K. Lin, F. Fuh Wong, Tetrahedron
2009, 65, 9592.
[18] A. Kimata, H. Nakagawa, R. Ohyama, T. Fukuuchi, S. Ohta,
T. Suzuki, N. Miyata, J. Med. Chem. 2007, 50, 5053.
[19] A. J. Kay, A. D. Woolhouse, G. J. Gainsford, T. G. Haskell,
C. P. Wyss, S. M. Giffin, I. T. McKinnie, T. H. Barnes, J. Mater.
Chem. 2001, 11, 2271.
[1]
a) H. Wissmann, H. J. Kleiner, Angew. Chem. 1980, 92, 129;
Angew. Chem. Int. Ed. Engl. 1980, 19, 133; b) R. Escher, P.
Bünning, Angew. Chem. 1986, 98, 264; Angew. Chem. Int. Ed.
Engl. 1986, 25, 277.
[2]
[3]
A. L. Llanes García, Synlett 2007, 8, 1328.
a) M. Desroses, K. Wieckowski, M. Stevens, L. R. Odell, Tetra-
hedron Lett. 2011, 52, 4417, and references cited therein; b) K.
Augustine, R. N. Atta, B. K. Ramappa, C. Boodappa, Synlett
2009, 20, 3378; c) G. M. Raghavendra, A. B. Ramesha, C. N.
Revanna, K. N. Nandeesh, K. Mantelingu, K. S. Rangappa,
Tetrahedron Lett. 2011, 52, 5571; d) X. Wen, J. El Bakali, R.
Deprez-Poulain, B. Deprez, Tetrahedron Lett. 2012, 53, 2440;
e) S. Poojari, P. Parameswar Naik, G. Krishnamurthy, Tetrahe-
dron Lett. 2012, 53, 4639; f) M. Jida, B. Deprez, New J. Chem.
2012, 36, 869.
a) J. K. Augustine, A. Bombrun, B. Ramappa, C. Boodappa,
Tetrahedron Lett. 2012, 53, 4422; b) G. Nagendra, C. Madhu,
T. M. Viswanatha, V. V. Sureshbabu, Tetrahedron Lett. 2012,
53, 5059; c) K. S. Sharath Kumar, T. R. Swaroop, K. B. Har-
sha, K. H. Narasimhamurthy, K. S. Rangappa, Tetrahedron
Lett. 2012, 53, 5619; d) J. K. Augustine, A. Bombrun, P. Ala-
garsamy, A. Jothi, Tetrahedron Lett. 2012, 53, 6280.
[20] H. Wilde, R. Herzschuh, P. Lepom, G. Mann, J. Prakt. Chem.
1981, 323, 14.
[4]
[5]
ˇ
[21] B. Stefane, S. Polanc, Tetrahedron 2007, 63, 10902.
[22] J. D. Wilson, T. D. Fulmer, L. P. Dasher, C. F. Beam, J. Hetero-
cycl. Chem. 1980, 17, 389.
[23] FR Patent 2240732 A1, 1974 [Chem. Abstr. 1975, 82, 28221].
[24] H. L. McPherson, B. W. Ponder, J. Heterocycl. Chem. 1976, 13,
909.
D. Castagnolo, F. Manetti, M. Radi, B. Bechi, M. Pagano, A. [25] Y. Toi, K. Isagawa, Y. Fushizaki, Nippon Kagaku Zasshi 1968,
De Logu, R. Meleddu, M. Saddi, M. Botta, Bioorg. Med.
Chem. 2009, 17, 5716.
89, 1096 [Chem. Abstr. 1969, 70, 87508].
[26] M. M. Mojtahedi, M. Javadpour, M. Saeed Abaee, Ultrason.
Sonochem. 2008, 15, 828.
[27] Z. Weihui, C. Xiao, S. Yanyan, J. Chem. Res. 2010, 34, 370.
[28] G. Rainer, U. S. Patent 3974176 A1, 1976.
[29] M. Balestra, H. Bunting, D. Chen, I. Egle, J. Forst, J. Frey, M.
Isaac, F. Ma, D. Nugiel, A. Slassi, G. Steelman, G. Sun, B.
Sundar, R. Ukkiramapandian, R. A. Urbanek, S. Walsh, WO
Patent 71730 A1, 2006.
[30] K. Amrein, D. Hunziker, B. Kuhn, A. Mayweg, W. Neidhart,
U. S. Patent 0049574 A1, 2007.
[31] J. De Mendoza, S. Garcia-Ochoa, P. Prados, E. Parra, Tetrahe-
dron 1986, 42, 2377.
[32] a) D. Castagnolo, A. De Logu, M. Radi, B. Bechi, F. Manetti,
M. Magnani, S. Supino, R. Meleddu, L. Chisu, M. Botta, Bi-
oorg. Med. Chem. 2008, 16, 8587; b) J. Lingling, T. Rui, X.
Xiumei, L. Ting, H. Wensai, L. Zicheng, W. Liang, Z. Yinglan,
K. Youfu, J. Chem. Res. 2012, 36, 691.
[6] F. Moreau, N. Desroy, J. M. Genevard, V. Vongsouthi, V.
Gerusz, G. Le Fralliec, C. Oliveira, S. Floquet, A. Denis, S.
Escaich, K. Wolf, M. Busemann, A. Aschenbrenner, Bioorg.
Med. Chem. Lett. 2008, 18, 4022.
[7] P. Manojkumar, T. K. Ravi, S. Gopalakrishnan, Eur. J. Med.
Chem. 2009, 44, 4690.
[8] R. Ramajayam, K. P. Tan, H. G. Liu, P. H. Liang, Bioorg. Med.
Chem. 2010, 18, 7849.
[9] T. Watanabe, M. Tahara, S. Todo, Cardiovasc. Ther. 2008, 26,
101.
[10] a) F. A. Pasha, M. Muddassar, M. M. Neaz, S. J. Cho, J. Mol.
Graphics Modell. 2009, 28, 54; b) M. F. Brana, A. Gradillas,
A. G. Ovalles, B. Lopez, N. Acero, F. Llinares, D. Munoz Min-
garro, Bioorg. Med. Chem. 2006, 14, 9; c) R. Tripathy, R. J.
McHugh, A. K. Ghose, G. R. Ott, T. S. Angeles, M. S. Albom,
Z. Huang, L. D. Aimone, M. Cheng, B. D. Dorsey, Bioorg.
Med. Chem. Lett. 2011, 21, 7261; d) M. H. Norman, L. Liu,
M. Lee, N. Xi, I. Fellows, N. D. D’Angelo, C. Dominguez, K.
Rex, S. F. Bellon, T. S. Kim, I. Dussault, J. Med. Chem. 2012,
55, 1858.
[33] J. B. Alderete, J. Belmar, M. Parra, C. Zuniga, Bol. Soc. Chil.
Quím. 2000, 45, 85.
Received: March 13, 2013
Published Online: July 29, 2013
Eur. J. Org. Chem. 2013, 5879–5885
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5885