Microwave-assisted synthesis utilizing supported reagents: A rapid and versatile synthesis of 1,5-diarylpyrazoles

Article abstract of DOI:10.1016/j.tetlet.2006.01.100

The application of microwave heating to a silica-assisted solution-phase synthesis technique has been utilized to develop a rapid and efficient two-step protocol for the preparation of pyrazoles from aryl methyl ketone and aryl hydrazine monomers.

Full text of DOI:10.1016/j.tetlet.2006.01.100

Tetrahedron Letters 47 (2006) 2443–2446
Microwave-assisted synthesis utilizing supported reagents: a
rapid and versatile synthesis of 1,5-diarylpyrazoles
Paul S. Humphries* and Jennifer M. Finefield
Pfizer Global R&D, Department of Medicinal Chemistry, 10614 Science Center Drive, San Diego, CA 92121, USA
Received 15 December 2005; revised 18 January 2006; accepted 19 January 2006
Available online 15 February 2006
Abstract—The application of microwave heating to a silica-assisted solution-phase synthesis technique has been utilized to develop a
rapid and efficient two-step protocol for the preparation of pyrazoles from aryl methyl ketone and aryl hydrazine monomers.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The utilization of supported reagents for the solution-
phase synthesis of both singletons and libraries has
become an increasingly applied tool for the preparation
of molecules of biological interest.1 One reason for this
escalation emanates from the appreciation that this
technology provides a beneficial method of performing
chemical transformations with minimal workup. More-
over, an ever-expanding collection of commercially
available supported reagents, for both synthesis and
purification,2 renders this technology more accessible.
reviewed.4 The conventional approach for pyrazole
formation is based on the condensation of substituted
hydrazines with 1,3-diketones or their equivalents, such
as b-ketoesters and b-cyanoketones. Limitations to this
approach are associated with scarce availability of
diversely substituted 1,3-diketones. As an alternative,
it became appealing to develop a two-step synthesis of
pyrazoles from aryl methyl ketones and aryl
hydrazines.5
The reaction of 4-methylacetophenone 1 with ethyl tri-
fluoroacetate 2 was carried out under a variety of condi-
tions (Table 1).5–7 The highest yielding non-microwave
conditions (entry 2) took 5 days to reach completion.
Elevated temperatures (entry 3) decreased the reaction
time to 2 h, although the yield was compromised. On
transferring these conditions into the microwave, the
desired enol ketone 3 was afforded in 10 min with an
excellent yield (entry 4).8,9
In a parallel medicinal chemistry (PMC) environment
this technology is appealing since excess amounts of
reagents can be used to drive reactions to completion.
This culminates in the production of libraries of higher
purity, which is advantageous for the development of
rapid SAR in medicinal chemistry programs. This is also
advantageous when subsequent modification or addi-
tional purification is required. In addition, when using
supported reagents reactions can be easily monitored
by conventional methods.
With an efficient method to prepare enol ketone 3 in
hand, optimization of the next step was undertaken.
Reaction of enol ketone 3 with 4-methylphenylhydr-
azine 4 was carried out under a variety of conditions
(Table 2).5,7 Firstly, the use of para-toluenesulfonic acid
in ethanol was attempted under non-microwave condi-
tions (100 ꢁC), with an excellent yield being obtained
in 7 h (entry 1). When these conditions were attempted
in the microwave (160 ꢁC) a 61% yield of pyrazole 5
was obtained (entry 2). On changing the acid source to
silica-supported toluenesulfonic acid,10 excellent yields
were obtained in both the thermal and microwave cases
(entries 3 and 4).
Aryl pyrazoles are ubiquitous substructures within a
diverse array of compounds with important biological
activity and pharmacological properties.3 The synthesis
of this eminent family of compounds has been well
Keywords: Pyrazole; Aryl methyl ketone; Aryl hydrazine; Silica-sup-
ported reagent; Microwave.
*
Corresponding author. Tel.: +1 858 622 7956; fax: +1 858 526
4438; e-mail: paul.humphries@pfizer.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.100

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P. S. Humphries, J. M. Finefield / Tetrahedron Letters 47 (2006) 2443–2446
Table 1. Effect of microwave heating on the reaction between 4-methylacetophenone 1 and ethyl trifluoroacetate 2
Entry
Base
Solvent
Method
Temp (ꢁC)
Time
Yield (%)
1
2
3
4
NaOMe
NaH
NaH
MTBE
DMF
DME
DME
Non-microwave
Non-microwave
Non-microwave
Microwave
25
25
100
160
14 h
5 days
2 h
25
88
60
95
NaH
10 min
Table 2. Effect of microwave heating and silica-supported acid source on the reaction between enol ketone 3 and 4-methylphenylhydrazine 4
Entry
Acid
Method
Temp (ꢁC)
Time
Yield (%)
1
2
3
4
pTsOH
pTsOH
Si-TsOH
Si-TsOH
Non-microwave
Microwave
Non-microwave
Microwave
100
160
100
160
7 h
5 min
6 h
95
61
84
95
5 min
When using the silica-supported reagent no work-up
was performed. The crude reaction mixture was evapo-
rated to dryness, and the resulting free flowing solid
purified directly by flash column chromatography.11
The optimum conditions for this reaction (entry 4)
yielded pyrazole 5 in 95% yield in 5 min.12
hydrazine addition to the resulting intermediates.
Schemes 1 and 2 highlight the efficiency of this approach
toward the synthesis of pyrazole analogues.13
In summary, we have described a rapid, convenient, and
high-yielding two-step protocol for the preparation
of pyrazoles. The procedure utilizes commercially
available reagents and equipment that are suitable for
the preparation of singletons or automated library
production.
With the above results in hand, we then pursued a
variety of targets by performing the microwave-assisted
enolate reaction followed by the microwave-assisted
Scheme 1. Targets accessed by microwave-assisted enolate formation.

P. S. Humphries, J. M. Finefield / Tetrahedron Letters 47 (2006) 2443–2446
2445
Scheme 2. Targets accessed by microwave-assisted pyrazole formation.
3. (a) Pargellis, C.; Tong, L.; Churchill, L.; Cirillo, P.;
Gilmore, G.; Graham, A. G.; Grob, P. A.; Hickey, E. R.;
Moss, N.; Pav, S.; Regan, J. Nature Struct. Biol. 2002, 9,
268–272; (b) Dumas, J.; Hatoum-Mokdad, H.; Sibley, R.;
Riedl, B.; Scott, W. J.; Monahan, M. K.; Lowinger, T. B.;
Brennan, C.; Natero, R.; Turner, T.; Johnson, J.; Schoen-
leber, R.; Bhargava, A.; Wilhelm, S. W.; Housley, T. J.;
Gerald, E. R.; Shrikhande, A. Bioorg. Med. Chem. Lett.
2000, 10, 2051–2054; (c) Menozzi, G.; Mosti, L.; Sche-
none, P.; Donnoli, D.; Schiariti, F.; Marmo, E. Farmaco
1990, 45, 167–186.
4. On the synthesis of pyrazoles and pyrazole related
structures see: (a) Hadad, N.; Baron, J. Tetrahedron Lett.
2002, 43, 2171–2173; (b) Makino, K.; Kim, H. S.;
Kurasawa, Y. J. Heterocycl. Chem. 1998, 35, 489–497;
(c) Elguero, J. Compr. Heterocycl. Chem. II 1996, 3, 1–75;
(d) Takagi, K.; Hubert-Habart, M. J. Heterocycl. Chem.
1996, 33, 1003–1015; (e) El-Rayyes, N. R.; Al-Awadi, N.
A. Synthesis 1985, 1028–1042; (f) Sammes, M. P.; Katri-
tzky, A. R. In Advances in Heterocyclic Chemistry;
Academic Press, 1983; Vol. 34; (g) Behr, L. C.; Fusco,
R.; Jarboe, C. H. In The Chemistry of Heterocyclic
Compounds; Weissberger, A., Ed.; Interscience Publishers,
John Wiley and Sons, 1967.
5. Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J.
S.; Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.;
Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier,
D. J.; Yu, S. S.; Andreson, G. D.; Burton, E. G.; Cogburn,
J. N.; Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.;
Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P.
C. J. Med. Chem. 1997, 40, 1347–1365.
6. Baxter, A. J. G.; Fuher, J.; Teague, S. J. Synthesis 1994,
207–211.
7. All microwave-assisted reactions were performed on either
a Biotage Emrys Creator or a Biotage Smith Synthesizer
(http://www.biotage.com).
Acknowledgements
The authors would like to thank Biotage AB for the sup-
ply of silica-based reagents, Shahnaz Ghassemi (Biotage
AB) for training and experimental procedures, and John
Tatlock for stimulating discussion and feedback on this
manuscript.
References and notes
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P. S. Humphries, J. M. Finefield / Tetrahedron Letters 47 (2006) 2443–2446
8. All new compounds were characterized by full spectro-
10. SiliCycle, Inc., http://www.silicycle.com.
scopic data, yields refer to chromatographed materials
with purity of >95%.
11. All purifications were performed on either a Biotage Sp1
or a Biotage Sp4 (http://www.biotage.com).
9. General procedure for the preparation of enol ketones. A
Smith Process Vial (2–5 mL) was charged with a stir bar,
sodium hydride (60% dispersion in mineral oil,
10 mmol), and dimethoxyethane (5 mL). To this solution
12. General procedure for the preparation of pyrazoles. A
Smith Process Vial (2–5 mL) was charged with a stir
bar, enol ketone 3 (0.45 mmol), and ethanol (5 mL). To
this solution was added Si-toluenesulfonic acid (1.5 mmol)
and 4-methylphenylhydrazine 4 (0.3 mmol). The reac-
tion vessel was sealed and heated at 160 ꢁC for 5 min
(fixed hold time) in a Biotage Emrys Creator. After
cooling, the vessel was uncapped and the reaction mixture
concentrated in vacuo. Purification (Biotage Sp4) by silica
gel chromatography (hexanes to ethyl acetate over 10
column volumes) afforded 5 (0.09 g, 95%) as a yellow
solid.
13. Although this work was performed in the 2–5 mL Smith
Process Vials, we see no reason why this chemistry cannot
be performed in the other Biotage vial formats. This will
presumably facilitate both library synthesis and scale-up
chemistry.
was added ethyl trifluoroacetate
2 (10 mmol) and
4-methylacetophenone 1 (5 mmol) dropwise. The reaction
vessel was sealed and heated at 160 ꢁC for 10 min (fixed
hold time) in a Biotage Emrys Creator. After cooling,
the vessel was uncapped and the reaction mixture
quenched with 2 M aqueous hydrochloric acid (10 mL).
This solution was then extracted with diethyl ether
(3 · 10 mL) and the combined organic extracts dried
(anhydrous magnesium sulfate), filtered, and concen-
trated in vacuo. Purification (Biotage Sp4) by silica gel
chromatography (hexanes to ethyl acetate over 10
column volumes) afforded 3 (1.09 g, 95%) as an orange
solid.