A practical, two-step synthesis of 1-alkyl-4-aminopyrazoles

Article abstract of DOI:10.1016/j.tetlet.2008.02.169

A novel synthesis of N1 alkyl-substituted pyrazoles with a free amino group at the C4 position is described. Commercially available 4-nitropyrazole was found to readily undergo Mitsunobu reactions with primary and secondary alcohols. Subsequent reduction of the nitro group via hydrogenation affords 1-alkyl-4-aminopyrazoles, which are valuable intermediates in the synthesis of pharmaceutically active compounds.

Full text of DOI:10.1016/j.tetlet.2008.02.169

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2996–2998
A practical, two-step synthesis of 1-alkyl-4-aminopyrazoles
Anna A. Zabierek, Kaleen M. Konrad, Andrew M. Haidle *
Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA
Received 31 January 2008; accepted 29 February 2008
Available online 4 March 2008
Abstract
A novel synthesis of N1 alkyl-substituted pyrazoles with a free amino group at the C4 position is described. Commercially available 4-
nitropyrazole was found to readily undergo Mitsunobu reactions with primary and secondary alcohols. Subsequent reduction of the
nitro group via hydrogenation affords 1-alkyl-4-aminopyrazoles, which are valuable intermediates in the synthesis of pharmaceutically
active compounds.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: 1-Alkyl-4-aminopyrazoles; Mitsunobu reaction
During the course of a medicinal chemistry lead optimi-
zation program, we wanted to replace an aniline that was
appended to our core. We were looking for isosteric groups
that would not only improve potency but also reduce lipo-
philicity, and we found that incorporation of 1-methyl-4-
aminopyrazole accomplished both of these goals (logD
with aniline fragment = 4.47; logD with 1-methyl-4-amino-
pyrazole fragment = 2.51). Additionally, pyrazole rings are
less likely to undergo oxidative metabolism than other 5-
Fig. 1. Comparison of cLogP values for aniline and 1-methyl-4-
aminopyrazole.
membered aromatic heterocycles, so we were interested in
exploring this new lead1 (Fig. 1).
with all of these methods is the lack of a large diversity
of commercially available hydrazines.
When we sought to expand the structure–activity
relationship (SAR) around the methyl group, we were sur-
prised to find a scarcity of commercially available 1-alkyl-
4-aminopyrazoles. Additionally, the number of published
routes to these compounds is fairly limited. The literature
methods use two types of building blocks as the source of
the 1-alkyl group, alkyl hydrazines and alkyl halides.
Hydrazines have been condensed with sodium nitromalon-
aldehyde,2 b-nitroenamines,3 2-(phenylacetamido)malon-
aldehyde,4 and most recently vinamidinium salts.5 With a
focus on generating SAR information, the main problem
The other option from the literature reports to produce
these intermediates involves alkylating a pyrazole nitrogen
followed by introduction of the 4-amino group. 4-Nitro-
pyrazole has been utilized in this fashion in the patent
literature, and subsequent reduction afforded the desired
1-alkyl-4-amino pyrazole.6 A recent report from workers
at AstraZeneca highlights the alkylation of 4-bromopyr-
azole followed by Buchwald–Hartwig coupling with benzo-
phenone imine, acidic deprotection, and free basing of the
resulting HCl salt.5 Again, the main limitation of these
methods from our perspective was the dearth of commer-
cially available alkyl halides of interest to us for our SAR
exploration.
*
As an alternative to the published methods, we were
intrigued by the possibility of using Mitsunobu chemistry
Corresponding author. Tel.: +1 617 992 2389; fax: +1 617 992 2406.
E-mail address: andrew_haidle@merck.com (A. M. Haidle).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.169

A. A. Zabierek et al. / Tetrahedron Letters 49 (2008) 2996–2998
2997
Table 1
1-Alkyl-4-aminopyrazoles produced via Scheme 1
Entry Alcohol starting 4-Aminopyrazole product
material
Two-step
yield (%)
Scheme 1. Reagents and conditions: (a) alcohol (2), PPh3, DBAD, THF,
20 °C; (b) H2, Pd/C, MeOH, 20 °C.
1
2
3
4
5
6
7
8
85
80
59
84
82
78
84
91
to append functionalized side chains at the pyrazole’s 1-
position (Scheme 1). This would allow us to use the large
commercial pool of functionalized alcohols as our diversity
source and to do so under mild reaction conditions that
would be compatible with the desired functionality. The
published7 pKa for 4-nitropyrazole is 9.64, so we reasoned
that it would behave as a competent nucleophile under
standard Mitsunobu conditions.8 Indeed, we found an iso-
lated literature example demonstrating the desired reactiv-
ity with a primary alcohol en route to synthesizing acyclic
nitropyrazole nucleosides.9 With this knowledge, we
explored the scope of our proposed two-step 1-alkyl-4-
amino pyrazole synthesis.
As the results shown in Table 1 indicate, primary alco-
hols, acyclic secondary alcohols, and cyclic secondary alco-
hols are good substrates for the initial Mitsunobu reaction.
Most alcohols react rapidly under the standard conditions,
with typical reactions reaching completion in under 30 min
(although often the reactions were left stirring overnight).
The crude reaction mixture was directly purified via silica
gel chromatography to give the 1-alkyl-4-nitropyrazole
intermediate, which was reduced via hydrogenation under
standard conditions to afford the desired 1-alkyl-4-amino-
pyrazoles without further purification.
From a medicinal chemistry standpoint, the pyrazoles
containing branched alkyl groups off the N1 position are
especially interesting. Compounds containing simple N-
primary alkyl groups (e.g., methyl and ethyl) are often N-
dealkylated through metabolic activation of the carbon
attached to the pyrazole nitrogen.1 We have found that
compounds containing pyrazoles with N-branched alkyl
substituents (e.g., the des-Boc version of 4h attached to
our core) are stable upon incubation with liver microsomes
(unpublished results).
In summary, we have developed a practical and efficient
two-step route to 1-alkyl-4-aminopyrazoles utilizing pri-
mary or secondary alcohols as the source of the alkyl
group. The large number of commercially available alco-
hols coupled with the mild reaction conditions described
herein allows ready access to diverse pyrazole building
blocks that should find use in medicinal chemistry lead
optimization programs.
judged complete according to LC/MS analysis, the reaction
mixture was concentrated and purified by silica gel flash
chromatography (1:9 ethyl acetate–hexanes, grading to
1:1 ethyl acetate–hexanes) to afford alcohol 3g (326.2 mg,
1
*
87%). H NMR (1.4:1 rotamer ratio, denotes peak due
to the minor rotamer, 500 MHz, DMSO-d6) d: 8.95 (s,
1H), 8.95* (s, 1H), 8.30 (s, 1H), 8.30* (s, 1H), 5.03 (m,
1H), 5.03* (m, 1H), 3.71 (m, 1H), 3.71* (m, 1H), 3.59 (d,
1H, J = 3.9 Hz), 3.56* (d, 1H, J = 4.1 Hz), 3.43 (m, 2H),
3.38* (m, 2H), 2.34* (m, 2H), 2.30 (m, 2H), 1.38* (s, 9H),
1.36 (s, 9H). LRMS (EI): Calculated for C12H18N4O4
[MÀt-Bu+H]+: 227.1, found 227.1.
Typical experimental procedure: To a solution of 4-nitro-
pyrazole (1) (150 mg, 1.33 mmol, 1.0 equiv), tert-butyl
3-hydroxypyrrolidine-1-carboxylate (2g) (248 mg, 1.33 mmol,
1.0 equiv), and triphenylphosphine (418 mg, 1.59 mmol,
1.2 equiv) in tetrahydrofuran (6.6 mL) under argon at
20 °C was added di-tert-butyl azodicarboxylate (397 mg,
1.725 mmol, 1.3 equiv) over 1 min. After the reaction was
A suspension of 3g (326.2 mg, 1.16 mmol, 1.0 equiv) and
10% palladium on carbon (123 mg, 0.116, 0.1 equiv) in
methanol (7 mL) was placed under a hydrogen atmosphere
by briefly evacuating the flask, then flushing with pure
hydrogen from a balloon. The black suspension was stirred
for 1 h at 20 °C before being filtered through a pad of

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A. A. Zabierek et al. / Tetrahedron Letters 49 (2008) 2996–2998
diatomaceous earth and washing with additional methanol.
Concentration of the filtrate yielded 4-aminopyrazole 4g
(280.2 mg, 1.11 mmol, 96%, 84% over two steps). 1H
NMR (1.3:1 rotamer ratio, * denotes peak due to the minor
rotamer, 500 MHz, DMSO-d6) d: 7.04 (s, 1H), 7.04* (s,
1H), 6.82 (s, 1H), 6.82* (s, 1H), 4.71 (m, 1H), 4.71* (m,
1H), 3.87 (br s, 2H), 3.87* (br s, 2H), 3.59 (m, 1H), 3.59*
(m, 1H), 3.44 (m, 1H), 3.42* (m, 1H), 3.36 (m, 2H), 3.32*
(m, 2H), 2.18 (m, 2H), 2.18* (m, 2H), 1.39* (s, 9H), 1.37
(s, 9H). LRMS (EI): Calculated for C12H20N4O2 [MÀt-
Bu+H]+: 197.1, found 197.1.
stability experiments, as well as Dr. Matthew Stanton for
helpful discussions and proofreading the manuscript.
References and notes
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O’Donnell, J. P. Chem. Res. Toxicol. 2002, 15, 269–299.
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4. Alberti, C.; Tironi, C.; Bainotti, F.; Deleide, G. Farmaco, Ed. Sci. 1977,
32, 92–105.
5. Hill, G. B.; Mortlock, A. A. Synthesis 2007, 1697–1701.
6. Jung, F. H.; Ple, P. WO Patent 2007099317, 2007.
7. Austin, M. W.; Blackborow, J. R.; Ridd, J. H.; Smith, B. V. J. Chem.
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Acknowledgments
8. Mitsunobu, O. Synthesis 1981, 1–28.
9. Walczak, K.; Wamberg, M.; Pedersen, E. B. Helv. Chim. Acta 2004, 87,
469–478.
The authors would like to thank Dr. Dapeng Chen and
Ms. Andrea Mislak for performing the in vitro microsomal