Microwave-assisted solution-phase synthesis of 1,4,5-trisubstituted pyrazoles

Article abstract of DOI:10.1002/ejoc.200390091

A small parallel library of 1,4,5-trisubstituted pyrazoles was prepared in solution using a three-step procedure starting from Meldrum acid. The Meldrum acid was acylated with different acyl chlorides and the products opened with different alcohols and amines to give substituted β-keto esters and β-keto amines. Further reaction with N,N-dimethylformamide dimethylacetal and the final cyclisation were effectively carried out under microwave irradiation. Scavenger resins were employed exclusively in the first step, whereas use of microwaves allowed complete conversion of the starting materials in the other two steps. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390091

FULL PAPER
Microwave-Assisted Solution-Phase Synthesis of 1,4,5-Trisubstituted Pyrazoles
Giampaolo Giacomelli,*[a] Andrea Porcheddu,[a] Margherita Salaris,[a] and
Maurizio Taddei*[b]
Keywords: Combinatorial chemistry / Heterocycles / Cyclization / Microwaves
A small parallel library of 1,4,5-trisubstituted pyrazoles was
prepared in solution using a three-step procedure starting
from Meldrum acid. The Meldrum acid was acylated with
different acyl chlorides and the products opened with differ-
ent alcohols and amines to give substituted β-keto esters and
carried out under microwave irradiation. Scavenger resins
were employed exclusively in the first step, whereas use of
microwaves allowed complete conversion of the starting mat-
erials in the other two steps.
β-keto amines. Further reaction with N,N-dimethylformam- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
ide dimethylacetal and the final cyclisation were effectively Germany, 2003)
The current development of new methods for the parallel supported regents. For these reasons, we considered the
synthesis of libraries of organic molecules has led to re- possibility to carry out as many steps as possible under mi-
newed interest in a technique in which individual organic
molecules are prepared in solution. The advantages of this
technique are the standard solution-phase reactivity of the
organic molecules, and easy analysis of the reaction using
conventional methods without any need for linker chem-
istry. A particularly important aspect is that the operational
time for the preparation of a new library can be shorter
than the time necessary to develop a reaction on solid
phase. On the other hand, in order to automate the pre-
paration of the library, all the steps must give pure com-
pounds after simple workup, involving exclusively filtration
or evaporation under vacuum. To reach this goal, polymer-
supported reagents have been employed frequently, and re-
cently the developments in the field have been reviewed
extensively.[1Ϫ5] The main drawbacks of polymer-assisted
solution-phase synthesis are related to the use of polymers
that show low loading values and difficulty in swelling in
several solvents. Moreover, the prices of several polymer-
supported reagents or scavengers are sometimes very high.
In order to prepare a library of pharmacologically relev-
ant heterocyclic scaffolds with a good level of potential mo-
lecular diversity in solution phase, we decided to optimize
the synthesis of a trisubstituted pyrazole to obtain a proto-
col that could be easily automated. We wanted to improve
the efficiency of each step to avoid purification and reduce
the work-up procedures for a limited number of expensive
crowave irradiation, as this technique has been generally ac-
cepted as a valuable aid in organic and combinatorial
synthesis.[6Ϫ10] We chose the pyrazole ring for its intrinsic
interest as the basic structure of several drugs,[11Ϫ16] and for
the possibility to have a trisubstituted scaffold with poten-
tial large molecular diversity. Substituted pyrazoles have al-
ready been prepared in the solid phase[17Ϫ21] and in
solution[22Ϫ25] following different synthetic strategies, where
hydrazine derivatives cyclise with 1,3-dicarbonyl or α,β-un-
saturated carbonyl compounds.
We decided to follow the retrosynthetic approach re-
ported in Scheme 1, originally described by Schenone and
co-workers,[26] and further employed by a group at Pfizer
to prepare a selective NHE-1 inhibitor.[27] The reaction in-
volved the cyclisation of a monosubstituted hydrazine with
an enamino- β-keto ester 1 derived from a simple β-keto
ester and N,N-dimethylformamide dimethyl acetal (DMF-
DMA). The sites for molecular diversity in this approach
are the substituents on hydrazine (R3), the derivatives of the
carboxylic function (ester OR2 or amide NHR2), and the
substituents on the starting β-keto ester (R1). Although sev-
eral β-keto esters are commercially available, in order to
obtain higher molecular diversity, we decided to prepare
compounds 2 by reaction of Meldrum acid with an acyl
chloride followed by ring-opening with different alcohols
or amines.
The first problem was to carry out the preparation of the
acyl Meldrum derivative 4 (Scheme 2) under conditions that
could be easily automated. As a model reaction, we treated
Meldrum acid with isobutanoyl chloride as described in the
literature.[28] After hydrolytic workup, the desired product 4
could be obtained in good yield and pure enough to be used
[a]
`
Dipartimento di Chimica, Universita degli Studi di Sassari,
Via Vienna 2, 07100 Sassari, Italy
E-Mail: ggp@uniss.it
[b]
`
Dipartimento Farmaco Chimico Tecnologico, Universita degli
Studi di Siena,
Via A.Moro, 53100 Siena, Italy
E-mail: taddei.m@unisi.it
Eur. J. Org. Chem. 2003, 537Ϫ541  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0203Ϫ0537 $ 20.00ϩ.50/0
537

G. Giacomelli, A. Porcheddu, M. Salaris, M. Taddei
FULL PAPER
Scheme 1
in the next step. To avoid the phase separation that follows
the hydrolytic workup and that is difficult to automate,
dichloromethane and pyridine contained in the reaction
mixture were evaporated under high vacuum and the prod-
uct 4 was extracted from the crude reaction mixture with
ethyl acetate. Different amounts of pyridine included in the
crude reaction mixture were extracted and removed by
passing the ethyl acetate solution through a short path col-
umn of an acidic resin (such as Amberlite-IRC 86). Evap-
oration of ethyl acetate gave good yields of the expected
acyl Meldrum derivative 4. This protocol was repeated us-
ing various acyl chlorides and the results found to be repro-
ducible. Unfortunately, we were not able to apply this pro-
cedure to interesting α-amino acid derivatives as they could
introduce an additional site for molecular diversity. The use
of mixed anhydrides, fluorides or other activating agents
always gave unsatisfactory results.[29]
Scheme 3
PS-DVP-supported sulfonyl chloride to the solution, fol-
lowed by a PS-DVB-supported tertiary amine. After filtra-
tion and evaporation of the solvent, the desired compounds
were obtained sufficiently pure for the next step.
In the reaction of the acyl Meldrum acids 4 with amines,
a stoichiometric amount of the nucleophile was needed.[31]
Consequently, pure amides 6 were isolated after one hour
in refluxing toluene after simple evaporation of the solvent.
The β-keto esters 5 and the β-keto amides 6 were further
reacted by refluxing in neat DMF-DMA as reported previ-
ously.[27] Employing 5 as a model compound and following
Scheme 2
The next step was the ring opening of 4 with different these conditions, the expected enamino keto ester was ob-
alcohols or amines to give β-keto esters 5 or β-keto amides tained in acceptable yields, although not acceptably pure
6 (Scheme 3). In the case of alcohols, the described proced- for the next step. We looked again for reaction conditions
ure employs a large excess of a volatile alcohol with respect compatible with automation. The desired product was isol-
to the Meldrum derivative.[30]
ated in good yields and with higher purity when the reac-
With the aim of optimising the conditions, we looked for tion was carried out at room temperature for longer time
ways to minimise the amount of alcohol needed for a suc- than when performed in refluxing solvent. Nevertheless, a
cessful transformation. Different conditions were tried, certain amount of the starting material was still present pre-
such as changing the solvent, the temperature, the concen- venting the use of the crude in the cyclisation. Moreover,
trations of the reagents, and adding also catalytic amounts due to the similar properties of the starting material and
of acid or base. Nevertheless, we found that with less than the products, it was impossible to find a scavenger that se-
three equiv. of alcohol the reaction does not reach an ac- lectively removes one in the presence of the other. In this
ceptable level of conversion to avoid chromatographic sep- case, the use of microwaves was crucial for the success of
aration from the starting material or other byproducts. The the reaction. In fact, submitting a solution of 5 in DMF-
best reaction condition was to reflux the Meldrum derivat- DMA to microwave irradiation (using a domestic oven un-
ive in the presence of three equiv. of the alcohol. The ap- der MORE conditions)[32Ϫ34] at 60 W for five minutes (five
plication of microwaves, in order to reduce the amount of cycles of 1 min followed by 1 min of rest) a complete con-
alcohol needed, gave no obvious improvements. Volatile al- version of the starting material was obtained and pure
cohols were preferentially employed in this step to simplify product 7 could be isolated after simple evaporation of
the final workup of removing the solvent under vacuum. DMF-DMA. The procedure was repeated with β-keto es-
When a less volatile alcohol, such as benzyl alcohol, was ters 5 and β-keto amides 6, which gave high yields of the
used, the excess of reagent could be removed by adding a desired products with a high level of purity.[35]
538
Eur. J. Org. Chem. 2003, 537Ϫ541

Microwave-Assisted Solution-Phase Synthesis of 1,4,5-Trisubstituted Pyrazoles
FULL PAPER
Products 7 and 8 were finally cyclised with a monosubsti-
tuted hydrazine hydrochloride in refluxing ethanol in the
presence of Et3N under nitrogen. After filtration of the in-
soluble components, the solvent was evaporated under va-
cuum and pyrazoles 9 or 10 were extracted from the crude
product with ethyl acetate or diethyl ether (Scheme 4). The
solution was passed through a short column of silica gel
and the solvents evaporated to give the expected product in
excellent yields and acceptable purity. To reduce the time
required for the final step (8 h under conventional heating)
the reaction was carried out under microwave irradiation,
allowing the formation of the desired pyrazole after heating
for eight minutes at 60 W (eight cycles of 1 min of heating
followed by 1 min of rest). The identity and the purity of
Following this protocol, a small parallel library was pre-
pared by choosing from a variety of distinctive groups to
create three varying sites of diversity (Table 1). As substitu-
ent R1, we added different aliphatic and aromatic groups
and as R2 we used different aliphatic, aromatic and hetero-
cyclic groups containing additional functionalities that
could be exploited for a further increase of diversity. The
chemoselectivity and the versatility of the process were
demonstrated by the preparation of pyrazoles having a pro-
tected amine at R2 (9{1,3,1}, 9{1,10,1}), or even a free car-
bonyl group (9{1,9,1}), susceptible to further functionalis-
ation. As substituent R3, we were limited to aromatic rings
due to the scarcity of commercially available monosubsti-
tuted hydrazines, although several hydrazines could be pre-
pared starting from aniline derivatives.[36] The steps that re-
quired the microwave assistance were carried out in sealed
tubes collected in a beaker and placed inside a modified
household apparatus that allowed an acceptable efficacy of
the process. Of course, the use of a parallel automated ap-
paratus that controls the microwave irradiation of any
single reactor will improve the protocol.
1
the products was determined by H and 13C NMR spectro-
scopy, and ES-MS analysis. The formation of the 1,4,5-tri-
substituted pyrazole was based on the resonance of the pyr-
azole proton at δ ϭ 7.9Ϫ8.1 ppm in the 1H NMR spectrum.
In conclusion, we have demonstrated that parallel librar-
ies of pharmacologically important compounds, such as tri-
substituted pyrazoles, can be prepared in the solution
phase. The correct choice of synthetic approach and the use
of microwaves limit as much as possible the use of expensive
supported reagents or scavengers which, in any case, were
successfully used in the first step. Moreover, the variety of
substrates employed here suggests the extension of the pro-
tocol to many other compounds to largely increase the mo-
lecular diversity.
Scheme 4
Table 1. Library of 1,4,5-trisubstituted pyrazoles 9 and 10
Compound
Empirical formula
MS [M ϩ H]ϩ
Found
Compound
Empirical formula
MS [M ϩ H]ϩ
Found
9{1-1-1}
9{1-2-1}
9{1-2-2}
9{1-3-2}
9{1-4-1}
9{1-5-1}
9{1-5-3}
9{2-1-1}
9{2-2-1}
9{2-3-1}
9{2-5-1}
9{2-5-2}
9{2-5-3}
9{2-6-1}
9{2-7-1}
9{2-8-1}
9{2-9-1}
9{2Ϫ10Ϫ1}
9{3-1-1}
9{3-3-1}
9{3-5-1}
C13H14N2O2
C14H24NO2
C14H23N3O4
C21H20N4O6
C14H16N2O2
C18H16N2O2
C13H13N3O3
C15H18N2O2
C16H18N2O2
C23H25N3O4
C20H20N2O3
C20H19N3O4
C15H17N3O3
C21H22N2O2
C20H28N2O3
C20H26N2O3
C19H22N2O3
C26H29N3O4
C16H20N2O2
C24H27N3O4
C21H22N2O2
231.6
243.7
287.6
425.4
245.3
293.6
260.6
259.7
271.6
408.5
321.6
366.5
287.5
335.5
345.4
343.5
327.4
448.7
273.5
421.5
334.4
9{3Ϫ10Ϫ1}
9{4-1-1}
9{4-2-1}
9{4-4-1}
9{4-9-1}
9{5-1-1}
9{5-2-1}
9{5-7-1}
9{5-9-1}
10{1-1-1}
10{1-2-1}
10{1-3-1}
10{2-2-1}
10{2-4-1}
10{2-5-1}
10{2-6-1}
10{2-7-1}
10{3-2-1}
10{4-1-1}
10{5-1-1}
10{5-2-1}
C27H31N3O4
C20H20N2O2
C21H20N2O2
C21H22N2O2
C24H24N2O3
C21H22N2O2
C22H22N2O2
C26H32N2O3
C26H30N2O3
C18H17N3O
C19H19N3O2
C19H19N3O
C21H23N3O2
C17H21N3O
C23H24N4O
C17H21N3O
C17H21N3O2
C22H25N3O2
C25H23N3O
C26H25N3O
C27H27N3O2
462.6
321.4
333.5
335.7
389.2
335.4
347.6
421.7
419.5
292.4
322.7
306.3
350.4
284.6
373.4
284.7
300.3
364.7
382.6
396.5
426.7
Eur. J. Org. Chem. 2003, 537Ϫ541
539

G. Giacomelli, A. Porcheddu, M. Salaris, M. Taddei
FULL PAPER
The same experimental procedure was followed using the products
reported in Schemes 2Ϫ4. All the pyrazoles were purified by pass-
ing through a short column of silica gel. The purity of all the prod-
ucts prepared was higher than 90% (HPLC-ESIMS analysis). The
following analytical data are representative of the library compon-
ents.
Experimental Section
Starting materials and reagents including PS-DVB supported re-
agents were purchased from Acros Organics (Geel, Belgium). The
reactions under microwave irradiation were carried out in a pres-
sure tube (SigmaϪAldrich) placed inside a domestic oven, con-
taining a beaker with water (200 mL), to modulate the microwave
energy input into the reaction mixture. Exposure to microwaves of
the sample was performed in cycles of one minute of irradiation
followed by at least one minute of rest. During the rest period the
hot water contained in the beaker was replaced.
1
Benzyl 5-Methyl-1-phenyl-1H-pyrazole-4-carboxylate [9{1-5-1}]: H
NMR (300 MHz, CDCl3): δ ϭ 2.54 (s, 3 H), 5.32 (s, 2 H),
7.31Ϫ7.53 (m, 10 H), 7.96 (s, 1 H) ppm. MS (ESI ϩve ion): m/z ϭ
293.6 [M ϩ H]ϩ
Benzyl 1-Carbamoyl-5-methyl--1H-pyrazole-4-carboxylate [9{1-5-
3}]: H NMR (300 MHz, CDCl3): δ ϭ 2.44 (s, 3 H), 5.20 (s, 2 H),
Except the model compounds described below, the components of
the library were characterized by HPLC-MS (ESI) through their
M ϩ 1 values (see Table 1).
1
7.30 (m, 5 H), 7.98 (s, 1 H), 8.56 (br. s, 2 H) ppm. MS (ESI ϩve
ion): m/z ϭ 260.6 [M ϩ H]ϩ
β-Keto Esters 5. General Procedure. 4-Methyl-3-oxopentanoic Acid
Benzyl Ester: Dry pyridine (0.098 g, 1.2 mmol) was slowly added,
followed by isobutanoyl chloride (0. 053 g, 0.5 mmol), to a solution
of Meldrum acid (0.072 g, 0.5 mmol) in dry CH2Cl2 (3 mL) in a
flask equipped with a magnetic stirrer at 0 °C. The mixture was
stirred at 0 °C for 1 h and at room temp. for an additional hour.
The solvent was evaporated under vacuum (1.5 Torr) and the crude
product was extracted with ethyl acetate (3 ϫ 3 mL). The fractions
were collected and passed through a short column filled with Am-
berlite-IRC-86 (1.0 g, previously swelled with MeOH). The Am-
berlite was washed with ethyl acetate (5 mL) and the collected
washings were dried over dry MgSO4 and evaporated under va-
cuum to give pure 4{2}. This product was dissolved in dry toluene
(8 mL); benzyl alcohol (0.162 g, 1.5 mmol) was added, and the mix-
ture was refluxed for 2 h. After cooling to room temperature, sul-
fonyl chloride polystyrene resin (0.7 g of 1.3 mmol/g loaded beads)
was added, followed by diisopropylaminomethyl polystyrene resin
(0.58 g of 2.4 mmol/g loaded beads). After stirring for 2 h, TLC
analysis showed the disappearance of benzyl alcohol. The solution
was filtered and the solvent evaporated to give pure 5{2Ϫ5}
(81 mg, 74% overall yield). The identity of the product was con-
(2-Benzyloxycarbonylaminoethyl) 5-Isopropyl-1-phenyl-1H-pyraz-
ole-4-carboxylate [9{2-3-1}]: 1H NMR (300 MHz, CDCl3): δ ϭ 1.19
(d, J ϭ 7 Hz, 6 H), 2.54 (m, 1 H), 3.38 (m, 2 H), 4.12 (m, 2 H),
5.10 (s, 2 H), 5.26 (br. s, 1 H), 7.35 (m, 10 H), 8.05 (s, 1 H) ppm.
MS (ESI ϩve ion): m/z ϭ 408.5 [M ϩ H]ϩ
Ethyl 5-Isopropyl-1-phenyl-1H-pyrazole-4-carboxylate [9{2-1-1}]:
1H NMR (300 MHz, CDCl3) : δ ϭ 1.30 (t, J ϭ 7 Hz, 3 H), 1.36
(d, J ϭ 7 Hz, 6 H), 3.25 (m, 1 H), 4.32 (q, J ϭ 7 Hz, 2 H), 7.48
(m, 5 H), 8.04 (s, 1 H) ppm. MS (ESI ϩve ion): m/z ϭ 259.7 [M
ϩ H]ϩ
(2-Phenylethyl)
5-Isopropyl-1-phenyl-1H-pyrazole-4-carboxylate
[9{2-6-1}]: 1H NMR (300 MHz, CDCl3) : δ ϭ 1.21 (d, J ϭ 7 Hz, 6
H), 2.79 (m, 2 H), 3.28 (m, 1 H), 4.27 (m, 2 H), 7.35 (m, 10 H),
8.00 (s, 1 H) ppm. MS (ESI ϩve ion): m/z ϭ 335.5 [M ϩ H]ϩ
(2-tert-Butoxy-1-methylethyl) 5-Isopropyl-1-phenyl-1H-pyrazole-4-
carboxylate [9{2-7-1}]: 1H NMR (300 MHz, CDCl3): δ ϭ 1.22 (s,
9 H), 1.26 (d, J ϭ 7 Hz, 6 H), 1.32 (d, J ϭ 7 Hz, 3 H), 2.99 (m, 1
H), 3.78 (m, 2 H), 4.17 (m, 1 H), 7.35 (m, 5 H), 8.09 (s, 1 H) ppm.
MS (ESI ϩve ion): m/z ϭ 345.4 [M ϩ H]ϩ
1
firmed by comparison of the H NMR and mass spectra with the
literature data.[37]
(4-Oxocyclohexyl)-1-Phenyl-5-phenylethyl-1H-pyrazole-4-carb-
oxylate [9{4-9-1}]: 1H NMR (300 MHz, CDCl3): δ ϭ 2.18 (m, 4
H), 2.78 (m, 4 H), 2.90 (m, 4 H), 4.14 (m, 1 H), 7.23Ϫ7.70 (m, 10
H), 7.89 (s, 1 H) ppm. MS (ESI ϩve ion): m/z ϭ 389.2 [M ϩ H]ϩ
β-Keto Amides 6. General Procedure: Compound 4, obtained as de-
scribed previously, was dissolved in dry toluene (5 mL) containing
allylamine (0.028 g, 0.5 mmol) and the mixture was refluxed under
nitrogen for 1 h. The solvent was evaporated to give pure 6{2Ϫ5}
(80 mg, 70% overall yield). The identity of the product was con-
N-(4-Methoxybenzyl)-5-isopropyl-1-phenyl-1H-pyrazole-4-carb-
oxyamide [10{2-2-1}]: 1H NMR (300 MHz, CDCl3): δ ϭ 1.20 (d,
J ϭ 7 Hz, 6 H), 2.78 (m, 1 H), 3.78 (s, 3 H), 4.39 (m, 2 H), 6.87,
7.02, 7.25, 7.50 (m, 11 H), 7.85 (s, 1 H) ppm. MS (ESI ϩve ion):
m/z ϭ 350.4 [M ϩ H]ϩ
1
firmed by comparison of the H NMR and mass spectra with the
literature data.[31]
Pyrazoles 9 and 10: Compound 5{2Ϫ5} (81 mg, 0.36 mmol) was
dissolved in DMF-DMA (0.8 mL) in a pressure tube that was
closed and placed inside a domestic microwave oven containing a
beaker filled with water. The tube was submitted to 3 cycles of
1 min of irradiation at 60 W followed by 1 min of rest. The tube
was cooled and the DMF-DMA was removed under vacuum. Ab-
solute ethanol (1 mL) was added to the crude product, followed by
phenylhydrazine hydrochloride (53 mg, 0.36 mmol) and Et3N (50
µL, 0.5 mmol). The tube was closed and submitted to 5 cyles of
1 min of irradiation at 60 W followed by 1 min of rest. The tube
was cooled and the solvent was evaporated. Ethyl acetate (5 mL)
was added and the solution was passed through a short column of
silica gel (1 g of silica gel for flash chromatography, eluent: ethyl
acetate). The solvent was removed to give the product 9{2-5-1},
N-Allyl-5-isopropyl-1-phenyl-1H-pyrazole-4-carboxyamide [10{2-4-
1}]: 1H NMR (300 MHz, CDCl3): δ ϭ 1.22 (d, J ϭ 7 Hz, 6 H),
2.98 (m, 1 H), 4.23 (m, 2 H), 5.16, 5.26 (two s, 2 H),6.08 (m, 1 H)
6.66 (br. s, 1 H) 7.25 (m, 5 H), 7.95 (s, 1 H) ppm. MS (ESI ϩve
ion): m/z ϭ 270.1 [M ϩ H]ϩ
N-[2-(3-Indolyl)ethyl]-5-isopropyl-1-phenyl-1H-pyrazole-4-carb-
oxyamide [10{2-5-1}]: 1H NMR (300 MHz, CDCl3): δ ϭ 1.26 (d,
J ϭ 7 Hz, 6 H), 2.88 (m, 1 H), 3.08 (m, 2 H), 3.97 (m, 2 H), 6.87,
7.02, 7.25, 7.85 (m, 11 H), 8.06 (s, 1 H), 10.6 (br. s, 1 H) ppm. MS
(ESI ϩve ion): m/z ϭ 373.4 [M ϩ H]ϩ
4-[(5-Isopropyl-1-phenyl-1H-pyrazole-4-yl)carbonyl]morpholine
HPLC purity 92% (84 mg, 93% yield). 1H NMR (300 MHz, [10{2-7-1}]: H NMR (300 MHz, CDCl3): δ ϭ 1.26 (d, J ϭ 7 Hz,
1
CDCl3) 1.39 (d, J ϭ 7 Hz, 6 H), 3.32 (m, 1 H), 5.36 (s, 2 H), 7.37 6 H), 2.78 (m, 1 H), 3.48 (m, 4 H), 4.29 (m, 4 H), 7.25 (m, 5 H),
(m, 10 H), 8.10 (s, 1 H) ppm. MS (ESI ϩve ion): 321.6 [M ϩ H]ϩ
7.95 (s, 1 H) ppm. MS (ESI ϩve ion): m/z ϭ 300.3 [M ϩ H]ϩ
Eur. J. Org. Chem. 2003, 537Ϫ541
540

Microwave-Assisted Solution-Phase Synthesis of 1,4,5-Trisubstituted Pyrazoles
FULL PAPER
[18]
S. R. Stauffer, J. A. Katzenellenbogen, J. Comb. Chem. 2000,
2, 318Ϫ329.
P. Groshe, A. Höltzel, T. B. Walk, A. W. Trautwein, G. Jung,
Synthesis 1999, 1961Ϫ1978.
A. C. Spivey, C. M. Diaper, H. Adams, A. J. Rudd, J. Org.
Chem. 2000, 65, 5253Ϫ5263.
Acknowledgments
This research was promoted and financially supported by Menarini
Ricerche (Pomezia, Italy).
[19]
[20]
[21]
[22]
[23]
[1]
S. J. Shuttleworth, S. M. Allin, R. D. Wilson, D. Nasturica,
A. L. Marzinzik, E. R. Felder, J. Org. Chem. 1998, 63,
723Ϫ727.
Synthesis 2000, 1035Ϫ1074.
J. Craig, M. S. Congreve, D. F. Emiabata-Smith, S. V. Ley, Syn-
[2]
B. A. Donohue, E. L. Michelotti, J. C. Reader, V. Reader, M.
Stirling, C. M. Tice, J. Comb. Chem. 2002, 4, 23Ϫ32.
S. R. Stauffer, Y. Huang, C. J. Coletta, R. Tedesco, J. A.
Katzenellenbogen, Bioorg. Med. Chem. 2001, 9, 141Ϫ150.
lett 2000, 1603Ϫ1612.
[3]
L. A. Thompson, Curr. Op. Chem. Biol. 2000, 4, 324Ϫ337.
[4]
S. V. Ley, I. R. Baxendale, R. N. Bream, P. S. Jackson, A. G.
Leach, D. A. Longbottom, M. Nesi, J. S. Scott, R. I. Storer, S.
[24]
[25]
´
R. G. J. Franzen, J. Comb. Chem. 2000, 2, 195Ϫ214.
J. Taylor, J. Chem. Soc., Perkin. Trans. 1 2000, 3815.
[5]
V. Molteni, M. H. Hamilton, L. Mao, C. M. Crane, A. P. Ter-
min, D. M. Wilson, Synthesis 2002, 1669Ϫ1674.
G. Menozzi, L. Mosti, P. Schenone, J. Heterocycl. Chem. 1987,
24, 1669Ϫ1674.
D. H. Drewry, D. M. Coe, S. Poon, Med. Chem. Rev. 1999,
2, 97Ϫ148.
[26]
[27]
[6]
V. Santagada, E. Perissutti, G. Caliendo, Curr. Med. Chem.
2002, 9, 1251Ϫ1283.
A. Lew, P. O. Krutzick, M. E. Hart, A. R. J. Chamberlin, J.
[7]
A. Guzman-Perez, R. T Wester, M. C. Allen, J. A. Brown, A.
R. Buchholz, E. R. Cook, W. W. Day, E. S. Hamanaka, S. P.
Kennedy, D. V. Knight, P. J. Kowalczyk, R. B. Marala, C. J.
Mularski, W. A. Novomisle, R. B. Ruggeri, W. R. Tracey, R. J.
Hill, Bioorg. Med. Chem. Lett. 2001, 11, 803Ϫ807.
Y. Oikawa, T. Yoshioka, K. Sugano, O. Yonemitsu, Org. Synth.
Coll. VII 1990, 359Ϫ361.
A. Bhandari, B. Li, M. A. Gallop, Synthesis 1999, 1951Ϫ1960.
Y. Oikawa, K. Sugano, O. Yonemitsu, J. Org. Chem. 1978, 43,
2087Ϫ2088.
G-S. Pak, H. C. Yang, B. Eun, Synthesis 1992, 1213Ϫ1214.
M. C. Daga, M. Taddei, G. Varchi, Tetrahedron Lett. 2001,
42, 5191Ϫ5194.
B. K. Banik, K. J. Barakat, D. R. Wagle, MS Manhas, A. K.
Bose, J. Org. Chem. 1999, 64, 5746.
A. K. Bose, M. S. Manhas, S. N. Ganguly, A. H. Sharma, B.
K. Banik, Synthesis 2002, 1578.
When the reaction was carried out under conventional heating
it took more than 3 h to go to completion.
M. G. Ferlin, G. Chiarelotto, O. Basadonna, O. Gia, S. Mobi-
lio, F. Baccichetti, F. Carlassare, Il Farmaco Ed. Sc. 1989, 44,
1141Ϫ1155.
Comb. Chem. 2002, 4, 95Ϫ105.
[8]
M. Larhed, A. Hallberg, Drug Disc. Today 2001, 6, 406.
[9]
P. Lidstrom, J. Tierney, B. Wathey, J. Westman, Tetrahedron
2001, 57, 9225Ϫ9283.
[28]
[10]
L. Perreux, A. Loupy, Tetrahedron 2001, 57, 9199Ϫ9223.
[11]
J-Y. Shim, W. J. Welsh, E. Cartier, J. L. Edwards, A. C. How-
[29]
[30]
lett, J. Med. Chem. 2002, 45, 1447Ϫ1458.
D. J. P. Pinto, M. J. Orwat, S. Wang, J. M. Fevig, M. L. Quan,
[12]
E. Amparo, J. Cacciola, K. A. Rossi, R. S. Alexander, A. M.
Smallwood, J. M. Lettgen, L. Liang, B. J. Aungst, M. R.
Wright, R. M. Knabb, J. Med. Chem. 2001, 44, 566Ϫ578.
[31]
[32]
[13]
D. L. Selwood, D. G. Brummel, J. Budworth, G. E. Burtin, R.
[33]
[34]
[35]
[36]
O. Campbell, S. S. Chana, I. G. Charles, P. A. Fernandez, R.
C. Glen, M. C. Goggin, A. J. Hobbs, M. R. Kling, Q. Liu, D.
J. Madge, J. Med. Chem. 2001, 44, 78Ϫ99.
[14]
S. R. Stauffer, C. J. Coletta, R. Tedesco, G. Nishiguchi, K.
Carlson, J. Sun, B. S. Katzenellenbogen, J. A. Katzenellen-
bogen, J. Med. Chem. 2000, 43, 4934Ϫ4947.
K. Kikuchi, S. Hibi, H. Yoshimura, K. Tai, T. Hida, N. Toku-
[15]
hara, T. Yamauchi, M. Nagai, Bioorg. Med. Chem. Lett. 2000,
10, 619Ϫ622.
[37]
[16]
W. L. Meyer, M. J. Brannon, C. G. Burgos, T. E. Goodwin, R.
P. G. Baraldi, P. Cozzi, C. Geroni, N. Mongelli, R. Romagnoli,
W. Howard, J. Org. Chem. 1985, 50, 438.
G. Spalluto, Bioorg. Med. Chem. Lett. 1999, 7, 251Ϫ262.
[17]
D.-M. Shen, M. Shu, K. T. Chapman, Org. Lett. 2000, 2,
Received July 8, 2002
2789Ϫ2792.
[O02366]
Eur. J. Org. Chem. 2003, 537Ϫ541
541