Microwave synthesis of 1-aryl-1H-pyrazole-5-amines

Article abstract of DOI:10.1016/j.tetlet.2018.11.060

A microwave-mediated synthesis of 1H-pyrazole-5-amines utilizing 1 M HCl at 150 °C was developed in order to provide products in a matter of minutes with minimal purification. Most reactions are complete in only 10 min and can be isolated via a simple filtration without the need for further purification by column chromatography or recrystallization. This method tolerates a range of functional groups and can be performed on milligram to gram scales.

Full text of DOI:10.1016/j.tetlet.2018.11.060

Accepted Manuscript
Microwave Synthesis of 1-Aryl-1H-pyrazole-5-amines
Nikalet Everson, Kenya Yniguez, Lauren Loop, Horacio Lazaro, Briana
Belanger, Grant Koch, Jordan Bach, Aashrita Manjunath, Ryan Schioldager,
Jarvis Law, Megan Grabenauer, Scott Eagon
PII:
S0040-4039(18)31407-2
https://doi.org/10.1016/j.tetlet.2018.11.060
TETL 50445
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
24 October 2018
19 November 2018
23 November 2018
Please cite this article as: Everson, N., Yniguez, K., Loop, L., Lazaro, H., Belanger, B., Koch, G., Bach, J.,
Manjunath, A., Schioldager, R., Law, J., Grabenauer, M., Eagon, S., Microwave Synthesis of 1-Aryl-1H-pyrazole-5-
amines, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.11.060
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Microwave Synthesis of 1-Aryl-1H-pyrazole-5-amines
Nikalet Eversona, Kenya Yniguezb, Lauren Loopc, Horacio Lazaroa, Briana Belangerc, Grant
Kochd, Jordan Bachc, Aashrita Manjunathc, Ryan Schioldagerc, Jarvis Lawc, Megan
Grabenauere and Scott Eagonc,*
aPromega Biosciences, 277 Granada Drive, San Luis Obispo, CA 93401, USA.
bSRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA.
cDepartment of Chemistry and Biochemistry, California Polytechnic State University, 1 Grand
Ave., San Luis Obispo, CA 93407, USA.
dDepartment of Chemistry & Biochemistry, University of California Santa Cruz, 1156 High
Street, Santa Cruz, CA 95064, USA.
eRTI International, 3040 East Cornwallis Road, P.O. Box 12194, Research Triangle Park, NC
27709, USA.
*Corresponding author. Email: seagon@calpoly.edu
Abstract
A microwave-mediated synthesis of 1H-pyrazole-5-amines utilizing 1M HCl at 150 °C
was developed in order to provide products in a matter of minutes with minimal purification.
Most reactions are complete in only 10 minutes and can be isolated via a simple filtration
without the need for further purification by column chromatography or recrystallization. This
method tolerates a range of functional groups and can be performed on milligram to gram
scales.
Keywords
Pyrazole-5-amines; Microwave; Heterocycles; Green Chemistry
Introduction
1-Aryl-1H-pyrazole-5-amines are reoccurring scaffolds and building blocks in a number
of biologically active compounds. Since their initial characterization,1 1-aryl-1H-pyrazole-5-
amines have appeared in pesticides,2 antimicrobials,3 kinase inhibitors,4 antileishmanial agents5
and chemotherapy candidates.6 Given their wide utility, a number of procedures have been
developed to prepare these compounds. A popular modern synthetic method involves the
extended reflux of an aryl hydrazine and 3-aminocrotonitrile in either acidic aqueous or alcoholic
solutions,7 followed by purification via chromatography and/or recrystallization. α-Cyanoketones
can be used in place of 3-aminocrotonitrile to generate a variety of 1-aryl-1H-pyrazole-5-amines
with additional substitutions at the 3-position. A number of reaction conditions have been
reported for this method as well, including heating at reflux for an extended period in toluene,8

alcohols9 and polyethylene glycol,10 yielding product after purification via extraction and/or
chromatography.
Our group became interested in the preparation of a variety of 1-aryl-1H-pyrazole-5-
amines for use in building more complex compounds as a part of our antimalarial studies.
Given the limited number of commercially available derivatives and the fact that we wished to
prepare compounds that were not reported in the literature, we sought to develop a method that
could produce 1-aryl-1H-pyrazole-5-amines in a quick, efficient manner with little or no required
purification. We recently reported our successful development of a microwave mediated
procedure for the rapid synthesis of β-carbolines,11 and we thought that a similar method could
be developed for pyrazole-5-amines. The literature contains a few references describing the
use of a microwave to prepare pyrazole-5-amines, but these reported methods have a number
of drawbacks. One report details the use of a conventional microwave utilizing toluene as a
solvent.12 This method requires several hours of heating, likely due to the fact that toluene is
known to be fairly transparent to microwave radiation, and offers little advantage to conventional
heating. Another paper detailed the use of methanol as the solvent, but again required long
reaction times and produced high reaction pressures.13 One additional paper reported the use
of ethanol as the solvent, but only reported a single compound and found that a full 4h of
heating were required, again offering little acceleration versus conventional heating methods.14
Results and Discussion
We decided to examine utilizing water as a solvent in the microwave given its status as a
“green” reagent, the fact that it readily absorbs microwave radiation, and its wide use in a
number of synthetic applications.15 We also reasoned that the product could be easily isolated
from the aqueous solution via addition of sufficient base to make the solution alkaline. We first
tested our hypothesis by reacting 3-aminocrotonitrile with a variety of commercially available
o
arylhydrazines, and were pleased to find that a 1M HCl solution at 150 C provides clean
product for substrates in a matter of minutes (Table 1). Most products were easily isolated by
making the reaction solution alkaline with 10% NaOH, then filtering to obtain the product in
excellent purity. In cases where no precipitation was observed, the product was instead
isolated with a liquid-liquid extraction using dichloromethane (1b and 1c). All products had
excellent purity as indicated by NMR spectroscopy and required no further purification by
chromatography or recrystallization (see ESI).
Table 1. Synthesis of N-aryl substituted 1H-pyrazole-5-amines from 3-aminocrotonitrile.
Timea
(min)
Isolated
Yield (%)
Entry
R
Product

1
1a
1b
10
10
84
90
2b
3b
4c
5
1c
1d
1e
1f
10
10
10
10
15
10
10
77
92
82
69
73
72
66
6
7
1g
1h
1i
8
9
b
c
aIndicated by TLC. Extracted with CH2Cl2. 1.5g scale.
We found that 1M HCl was the optimal concentration of acid for use with this procedure,
as higher concentrations of HCl provided no significant acceleration of the observed reaction
times, while much lower concentrations of HCl caused solubility issues with some substrates.
We also found that a temperature of 150 °C gave sufficiently short reaction times, while avoiding
degradation of starting reagents and maintaining vessel pressures below 10 bar. While higher
temperatures can certainly be used for some substrates, we prefer to always keep operating
pressures below 10 bar as a matter of safety. Interestingly, we found that the heterocycle 4-
1
hydrazinopyridine failed to provide product, with H-NMR spectroscopy indicating a complex
mixture of by-products. However, our method did tolerate a number of other functional groups,

including alkyl, halogen, nitrile and nitro groups. We also found that our conditions worked on
both the milligram and gram scale, as we were able to prepare compound 1d on both the
milligram and gram scale with no apparent change in observed reaction times or yields.
Next, we turned our attention to introducing more complex substituents at the 3-position
by using α-cyanoketones. We prepared the desired α-cyanoketones from their respective
brominated precursors following a previously published procedure,16 then combined them with
phenylhydrazine under the same conditions used above (Table 2).
Table 2. Synthesis of 1H-pyrazole-5-amines from α-cyanoketones.
Timea
(min)
Isolated
Yield (%)
Entry
1
R
Product
2a
10
10
78
87
2
3
2b
2c
10
96
4
5b
6
2d
2e
2f
10
10
10
79
76
94

7
2g
35
74
8c
2h
2i
20
10
84
89
9
b
c
aIndicated by TLC. Made alkaline with NaHCO3. Extracted
with CH2Cl2.
Most substrates tested provided products in moderate to excellent yields after only 10 minutes
of irradiation, with two compounds requiring slightly longer reaction times (2g and 2h).
Interestingly, we found that both m-nitrophenyl and p-nitrophenyl-3-oxopropanenitrile failed to
fully react with phenylhydrazine, even after more than 2.5h of heating. However, our reaction
conditions did tolerate a number of other functionalized aromatic groups including a
trifluoromethyl group and a methyl sulfone. We were also able to readily isolate a p-
hydroxyphenyl derivative (2e) by utilizing sodium bicarbonate instead of sodium hydroxide in the
isolation step. Our conditions also tolerated a 2-furanyl heterocycle, as well as a tert-butyl
substituent. All compounds were precipitated and isolated via a simple filtration in excellent
purity with the exception of the 2-furanyl derivative, which was isolated by a liquid-liquid
extraction with CH2Cl2.
Conclusion
The microwave reaction of arylhydrazines with 3-aminocrotonitrile at 150 °C in 1M HCl
readily provides 1H-pyrazole-5-amines in 10-15 minutes, with most products isolated in
moderate to excellent yields after a simple filtration. The use of α-cyanoketones with
phenylhydrazine under the same conditions also yields a number of functionalized 1H-pyrazole-
5-amines in a matter of minutes. A total of 18 compounds were prepared with yields ranging
from 66-96%, with isolated product masses ranging from the milligram to gram scale. All
isolated compounds were of excellent purity by NMR and required no chromatography or
recrystallization. This procedure is significantly faster than other reported procedures, and most
substrates only require aqueous solutions during reaction and isolation. This procedure also
tolerates a broad range of functional groups, including halides, nitriles, phenols, sulfones and
various alkyl-substituted aromatic rings.
Acknowledgements
This work was supported by the Bill and Linda Frost Fund.
Supporting Information
Supplementary data including synthetic procedures and characterization data for all
reported compounds can be found at (INSERT WEB ADDRESS HERE)

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Highlights



Pyrazole-5-amines appear in molecules with a diverse range of activities
A microwave-mediated method was developed to produce products in minutes
Products can be isolated with a simple filtration using only water as the solvent