Synthesis of novel 4-fluoro-2H-pyrazol-3-ylamines

Article abstract of DOI:10.1080/00397910903277912

A new and efficient synthesis for the preparation of novel 4-fluoro-2H-pyrazol-3-ylamines is described. It involves the reaction of an acyl chloride with fluoroacetonitrile and sequential ring closure of the-fluoro-ketonitrile with hydrazine. Utilizing this synthetic protocol, we have synthesized a variety of 4-fluoro-2H-pyrazol-3-ylamines with different steric and electronic demands. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903277912

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Synthesis of Novel 4-Fluoro-2H-
pyrazol-3-ylamines
Giuseppe Cocconcelli a , Chiara Ghiron a , Simon Haydar b , Iolanda
Micco a & Riccardo Zanaletti a
a Siena Biotech S.p.A. , Siena, Italy
b Chemical Sciences and Neuroscience Discovery Research, Wyeth
Research , Princeton, New Jersey, USA
Published online: 05 Aug 2010.
To cite this article: Giuseppe Cocconcelli , Chiara Ghiron , Simon Haydar , Iolanda Micco & Riccardo
Zanaletti (2010) Synthesis of Novel 4-Fluoro-2H-pyrazol-3-ylamines, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:17, 2547-2555,
DOI: 10.1080/00397910903277912
To link to this article: http://dx.doi.org/10.1080/00397910903277912
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Synthetic Communications1, 40: 2547–2555, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903277912
SYNTHESIS OF NOVEL 4-FLUORO-2H-
PYRAZOL-3-YLAMINES
Giuseppe Cocconcelli,1 Chiara Ghiron,1 Simon Haydar,2
Iolanda Micco,1 and Riccardo Zanaletti1
1Siena Biotech S.p.A., Siena, Italy
2Chemical Sciences and Neuroscience Discovery Research, Wyeth Research,
Princeton, New Jersey, USA
A new and efficient synthesis for the preparation of novel 4-fluoro-2H-pyrazol-3-ylamines is
described. It involves the reaction of an acyl chloride with fluoroacetonitrile and sequential
ring closure of the a-fluoro-b-ketonitrile with hydrazine. Utilizing this synthetic protocol,
we have synthesized a variety of 4-fluoro-2H-pyrazol-3-ylamines with different steric and
electronic demands.
Keywords: Aminopyrazole; fluoro; 4-fluoro-2H-pyrazol-3-ylamines
The pyrazole ring continues to attract wide interest in medicinal chemistry.
Compounds containing this heterocycle show a broad range of biological activities,
including analgesic,[1] antimicrobial,[2] anti-inflammatory,[3] hypoglycemic,[4] and
antihypertensive[5] activities. In particular, 3-aminopyrazole derivatives (3-AP, Fig. 1)
have been reported as protein b-sheet stabilizers[6] and are largely used as building
blocks for the preparation of molecules with potential biological activity.[7,8] 3-AP
and their syntheses are widely described in the literature.[9–11]
These aminopyrazoles are usually prepared according to Scheme 1, in which the
b-ketonitriles, obtained by the treatment of esters with CH3CN and NaH=toluene
or n-BuLi=tetrahydrofuran (THF), are cyclized with hydrazine in ethanol.
Recently, we have been interested in replacing the hydrogen in position 4 of
these derivatives (3-AP) with fluorine (Fig. 1). The substitution of hydrogen atoms
with fluorine is a very common strategy in medicinal chemistry and is widely used
to improve the profile of a drug candidate.[12]
However, although the introduction of other halogens into the amino pyrazole
core has been described in the literature,[13,14] very few examples have been reported
on the synthesis of 4-fluoro-2H-pyrazol-3-ylamines (4-F-3-AP, Fig. 1). In these
examples, fluorine has been introduced on the pyrazole ring using fluorinating agents
Received August 11, 2009.
Address correspondence to Riccardo Zanaletti, Siena Biotech, Med Chem, strada del Petriccio e
Belriguardo, Siena, 53100 Italy. E-mail: rzanaletti@sienabiotech.it
2547

2548
G. COCCONCELLI ET AL.
Figure 1. Generic structure of 3-AP and 4-F-3-AP.
such as Selectfluor.[15] These reactions suffer from low general applicability,
formation of a series of potential side products, and poor yields.
We investigated different synthetic approaches to prepare 4-F-3-AP, avoiding
the use of fluorinating agents and their related drawbacks.
We initially explored the synthesis by applying the procedure reported for
3-AP, utilizing FCH2CN instead of CH3CN (Scheme 2). As a model compound,
and to validate the approach, we utilized methyl benzoate as the starting material.
Scheme 1. Generic procedure for the synthesis of 3-AP.
Scheme 2. Validation for the synthesis of 4-F-3-AP.

NOVEL 4-FLUORO-2H-PYRAZOL-3-YLAMINES
2549
Table 1. Validation of the synthesis of a-fluoro-b-ketonitrile
Entry
X
Base
Sequence addition
Resulta
1
2
3
4
5
6
ꢁOMe
ꢁOMe
ꢁOMe
ꢁCl
n-BuLi
LDA
LDA
C-B-A
C-B-A
C-A-B
C-A-B
C-A-B
C-A-B
No conversion
No conversion
Product in traces
50% conversion
No conversion
95% conversion
LDA
BTPP
LHMDS
ꢁCl
ꢁCl
aEvaluated by LCMS of the crude solution.
The effect of different addition conditions on the reaction outcome was investigated
(Scheme 2, Table 1).
After the initial attempt with n-BuLi failed (entry 1), we examined the use of
lithium diisopropylamide (LDA) as a less nucleophilic base (entry 2), to avoid the
possible side reaction of n-BuLi with methyl benzoate. Both experiments failed,
possibly because of the lower reactivity of the anion of FCH2CN compared to the
anion of CH3CN.
Knowing that the possibility for FCH2CN to polymerize in the presence of a
base was likely, we decided to reverse the addition of reagents to limit the concen-
tration of anion formed in the reaction (entry 3). With this change, traces of the
desired b-ketonitrile were detected in the liquid chromatography–mass spectrometry
(LCMS) chromatogram of this reaction, confirming the approach.
We believed that the nucleophilicity of the anion of FCH2CN was not sufficient
for the reaction with a moderately electrophilic ester, so the acyl chloride was chosen
in an attempt to increase the reactivity (entry 4). The 50% conversion confirmed the
need for more reactive acyl chlorides. A simple screen for alternative bases allowed
optimization of the reaction approach. The use of phosphazene base tert-butylimino-
tri(pyrrolidino)phosphorane (BTPP, entry 5) was unsuccessful, while lithium bis(tri-
methylsilyl)amide (LHMDS, entry 6) afforded near quantitative yield of the desired
penultimate intermediate. The subsequent ring closure to 4-F-3-AP was achieved by
refluxing the a-fluoro-b-ketonitrile with NH2NH2 ꢀ H2O in ethanol. These conditions
were applied to a small set of molecules, selecting commercially available acyl chlor-
ides with different electronic and steric demands to evaluate the scope of the reaction
(Table 2).
All products were isolated and characterized by NMR and high-performance
liquid chromatography (HPLC). Both aromatic and aliphatic acyl chlorides gave
the desired products in moderate to good yields, demonstrating the extendibility
and reliability of the reaction conditions.
In an attempt to broaden the scope of this reaction, we examined the appli-
cation of the same conditions to phenacetyl chlorides. To our dismay, this resulted
in a drastic change in the reaction profile. In this case, the competitive reaction
between two phenacetyl chloride molecules was predominant, and total conversion
to 5-benzyl-4-phenyl-1H-pyrazol-3-ol was observed (13, Scheme 3).
In summary, a new and efficient synthesis of novel 4-fluoro-3-aminopyrazoles
was developed, and its utility was showcased in the preparation of a small set of
molecules obtained in fair to good yields.

2550
G. COCCONCELLI ET AL.
Table 2. Yields of 4-F-3-AP (isolated yields over two steps)
Compound
1
R
Yield (%)
52
2
3
4
37
55
39
5
6
7
54
40
74
8
9
45
74
41
10
11
12
68
37

NOVEL 4-FLUORO-2H-PYRAZOL-3-YLAMINES
2551
Scheme 3. Application of the conditions described to phenacetyl chloride.
The order of addition of the reagents and the choice of base were fundamental
factors contributing to the success of the approach. This reaction is applicable to
both aromatic and aliphatic acyl chlorides, with the exception of phenacetylchloride
(and probably analog molecules).
EXPERIMENTAL
General Experimental Method
All solvents and reagents were used as supplied, unless otherwise stated.
Reactions using air=moisture-sensitive reagents were run under a nitrogen atmos-
phere. Purifications were performed with flash silica-gel cartridges from Merck.
All thin-layer chromatographic (TLC) analyses were performed on silica gel, and
spots were revealed by ultraviolet (UV) visualization at 254 nm and KMnO4 stain.
Characterization of the compounds 1–13 was determined by HRMS; NMR spectra
were recorded using a 400-MHz spectrometer. Chemical shifts are reported in parts
per million referred to the solvent (s: singlet, d: doublet, t: triplet, dd: double doublet,
m: multiplet). LCMS 5- and 10-min methods were run with 0.1% formic acid=water
and 0.1% formic acid=acetonitrile with gradients 5=95 to 95=5 using C18, 3-mm,
2.0- ꢂ 50.0-mm column. Electrospray ionization (ESI) and photodiode array
(PDA) detection were used.
Generic Procedure for 4-Fluoro-2H-Pyrazol-3-ylamines
A 1 M solution of LHMDS in THF (10 mL, 10.0 mmol, 2.0 eq) was added
dropwise to a solution of acyl chloride (5.0 mmol, 1.0 eq) and FCH2CN (278 mL,
5.0 mmol, 1.0 eq) in dry THF (15 mL) cooled to ꢁ78 ꢃC under nitrogen. The
mixture was allowed to reach room temperature, and 1N HCl was added dropwise
at pH 2. The mixture was concentrated under reduced pressure to afford the desired
a-fluoro-b-ketonitrile in a form pure enough for the next step.

2552
G. COCCONCELLI ET AL.
Hydrazine monohydrate (582 mL, 12.0 mmol, 2.4 eq) was added to a solution of
the a-fluoro-b-ketonitrile (5.0 mmol) in EtOH (15 mL), and the reaction was heated
at reflux for 18 h. The reaction mixture was allowed to cool to room temperature,
and the solvent was evaporated under reduced pressure. The residue was dissolved
in dichloromethane (DCM) and washed with water. The organic phase was concen-
trated to give a crude product that was purified by SiO2 column. Yields were between
37% and 74%.
Spectroscopic and Analytical Data
4-Fluoro-5-(4-methyoxy-phenyl)-2H-pyrazol-3-ylamine (1). Following the
general procedure described previously, 538 mg of title compound were obtained
1
as a light brown powder (52% yield). H NMR (400 MHz, acetone-d6) d (ppm):
3.83 (s, 3H), 4.34 (s, 2H), 7.02 (d, J ¼ 8.98 Hz, 2H), 7.65 (d, J ¼ 8.48 Hz, 2H),
10.99 (s, 1H). 19F NMR (376 MHz, acetone-d6) d (ppm): ꢁ190.55 (s, 1F). MS
(ESI): m=z 208 [M þ Hþ]þ; LC Rt ¼ 2.00 min (10-min method). HRMS calcd. for
C10H11FN3O 208.08807; found 208.08823.
5-Cyclopropyl-4-fluoro-2H-pyrazol-3-ylamine (2). Following the general
procedure described previously, 261 mg of title compound were obtained as a light
1
brown powder (37% yield). H NMR (400 MHz, DMSO-d6) d (ppm): 0.66–0.70
(m, 2H), 0.79–0.84 (m, 2H), 1.67–1.74 (m, 1H), 4.50 (s, 2H), 11.11 (s, 1H). 19F
NMR (376 MHz, DMSO-d6) d (ppm): ꢁ193.076 (s, 1F). MS (ESI): m=z 142
[M þ Hþ]þ; LC Rt ¼ 0.53 min (10-min method). HRMS calcd. for C6H9FN3
142.07750; found 142.07730.
4-Fluoro-5-phenyl-2H-pyrazol-3-ylamine (3). Following the general pro-
cedure described, 563 mg of title compound were obtained as a light brown powder
1
(55% yield). H NMR (400 MHz, DMSO-d6) d (ppm): 4.80 (s, 2H), 7.28–7.32 (m,
1H), 7.41–7.45 (m, 2H), 7.62–7.64 (m, 2H), 11.88 (s, 1H). 19F NMR (376 MHz,
DMSO-d6) d (ppm): ꢁ186.91 (s, 1F). MS (ESI): m=z 178 [M þ Hþ]þ; LC
Rt ¼ 1.92 min (10-min method). HRMS calcd. for C9H9FN3 178.07750; found
178.07728.
5-(4-Ethyl-phenyl)-4-fluoro-2H-pyrazol-3-ylamine (4). Following the
general procedure described, 399 mg of title compound were obtained as a light
brown powder (39% yield). 1H NMR (400 MHz, acetone-d6) d (ppm): 1.23 (t,
J ¼ 7.60 Hz, 3H), 2.66 (q, J ¼ 7.60 Hz, 2H), 4.36 (s, 2H), 7.64 (d, J ¼ 8.19 Hz, 2H),
7.30 (d, J ¼ 8.24 Hz, 2H), 11.01 (s, 1H). 19F NMR (376 MHz, acetone-d6) d (ppm):
189.71 (s, 1F). MS (ESI): m=z 206 [M þ Hþ]þ; LC Rt ¼ 2.73 min (10-min method).
HRMS calcd. for C11H13FN3 206.10880; found 206.10865.
4-Fluoro-5-(6-trifluoromethyl-pyridin-3-yl)-2H-pyrazol-3-ylamine
(5).
Following the general procedure described, 246 mg of title compound were obtained
as a light brown powder (54% yield). 1H NMR (400 MHz, acetone-d6) d (ppm): 7.95
(d, 1H, J ¼ 8.24 Hz), 8.42 (d, 1H, J ¼ 8.24 Hz), 9.17 (s, 1H). 19F NMR (376 MHz,
acetone-d6) d (ppm): ꢁ68.77 (s, 3 F), ꢁ178.84 (s, 1F). MS (ESI): m=z 247 [M þ Hþ]þ;
LC Rt ¼ 2.28 min (10 min method). HRMS calcd. for C9H7F4N4 247.06014; found
247.06003.

NOVEL 4-FLUORO-2H-PYRAZOL-3-YLAMINES
2553
4-Fluoro-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-ylamine (6). Follow-
ing the general procedure described, 490 mg of title compound were obtained as a
1
light brown powder (40% yield). H NMR (400 MHz, DMSO-d6) d (ppm): 4.96
(s, 2H), 7.79 (d, 2H, J ¼ 8.47 Hz), 7.86 (d, 2H, J ¼ 8.26 Hz), 12.14 (s, 1H). 19F
NMR (376 MHz, DMSO-d6) d (ppm): ꢁ61.96 (s, 4 F), ꢁ191.70 (s, 1F). MS (ESI):
m=z 246 [M þ Hþ]þ; LC Rt ¼ 1.97 min (5-min method). HRMS calcd. for
C10H8F4N3 246.06489; found 246.06472.
5-(4-Chloro-phenyl)-4-fluoro-2H-pyrazol-3-ylamine (7). Following the
general procedure described, 780 mg of title compound were obtained as a light
1
brown powder (74% yield). H NMR (400 MHz, DMSO-d6) d (ppm): 4.88 (s, 2H),
7.50 (d, 2H, J ¼ 8.4 Hz), 7.65 (d, 2H, J ¼ 8.4 Hz). 19F NMR (376 MHz, DMSO-d6)
d (ppm): ꢁ189.06 (s, 1F). MS (ESI): m=z 212 [M þ Hþ]þ; LC Rt ¼ 2.61 min
(10-min method). HRMS calcd. for C9H8ClFN3 212.03853; found 212.03837.
5-tert-butyl-4-fluoro-2H-pyrazol-3-ylamine (8). Following the general
procedure described, 353 mg of title compound were obtained as a light brown
1
powder (45% yield). H NMR (400 MHz, acetone-d6) d (ppm): 1.32 (s, 9H), 4.07
(s, 2H), 10.35 (s, 1H). 19F NMR (376 MHz, acetone-d6): d (ppm): ꢁ189.83 (s, 1F).
MS (ESI): m=z 158 [M þ Hþ]þ; LC Rt ¼ 1.20 min (5-min method). HRMS calcd.
for C7H13FN3 158.10880; found 158.10867.
4-Fluoro-5-thiophen-2-yl-2H-pyrazol-3-ylamine (9). Following the general
procedure described, 677 mg of title compound were obtained as a light brown powder
(74% yield). 1H NMR (400 MHz, acetone-d6) d (ppm): 4.56 (s, 2H), 7.14–7.17 (m, 1H),
7.40–7.42 (m, 1H), 7.49–7.52 (m, 1H), 11.18 (s, 1H). 19F NMR (376 MHz, acetone-d6)
d (ppm): ꢁ180.37 (s, 1F). MS (ESI): m=z 184 [M þ Hþ]þ; LC Rt ¼ 1.78 min (10-min
method). HRMS calcd. for C7H7FN3S 184.03392; found 184.03380.
5-Cyclopentyl-4-fluoro-2H-pyrazol-3-ylamine (10). Following the general
procedure described, 346 mg of title compound were obtained as a light brown
1
powder (41% yield). H NMR (400 MHz, acetone-d6) d (ppm): 1.61–1.79 (m, 6H),
1.96 ꢁ 2.06 (m, 2H), 2.95–3.06 (m, 1H), 4.09 (s, 1H), 10.40 (s, 1H). 19F NMR
(376 MHz, acetone-d6) d (ppm): ꢁ193.04 (s, 1F). MS (ESI): m=z 170 [M þ Hþ]þ;
LC Rt ¼ 1.63 min (10-min method). HRMS calcd. for C8H13FN3 170.10880; found
170.10899.
4-Fluoro-5-pyridin-3-yl-2H-pyrazol-3-ylamine (11). Following the general
procedure described, 605 mg of title compound were obtained as a light brown
powder (68% yield). 1H NMR (400 MHz, DMSO-d6) d (ppm): 4.95 (s, 2H),
7.44–7.49 (m, 1H), 7.97–8.00 (m, 1H), 8.49–8.51 (m, 1H), 8.85–8.87 (m, 1H), 12.03
(s, 1H). 19F NMR (376 MHz, DMSO-d6) d (ppm): ꢁ189.96 (s, 1F). MS (ESI): m=z
178 [M þ Hþ]þ; LC Rt ¼ 0.21 min (10-min method). HRMS calcd. for C8H8FN4
179.07275; found 179.07250.
4-Fluoro-5-quinolin-2-yl-2H-pyrazol-3-ylamine (12). Following the general
procedure described, 421 mg of title compound were obtained as a light brown pow-
der (37% yield). 1H NMR (400 MHz, DMSO-d6) d (ppm): 4.83 (s, 2H), 7.57–7.62 (m,
1H), 7.76–7.82 (m, 2H), 7.91–8.00 (m, 2H), 8.41–8.46 (m, 1H), 12.26 (s, 1H). 19F
NMR (376 MHz, DMSO-d6) d (ppm): ꢁ186.02 (s, 1F). MS (ESI): m=z 229

2554
G. COCCONCELLI ET AL.
[M þ Hþ]þ; LC Rt ¼ 2.07 min (10-min method). HRMS calcd. for C12H10FN4
229.08840; found 229.08825.
5-Benzyl-4-phenyl-1H-pyrazol-3-ol (13). Following the general procedure
described, 650 mg of title compound were obtained as a light brown powder (52%
yield). 1H NMR (400 MHz, DMSO-d6) d (ppm): 2.83 (s, 2H), 4.14 (s, 2H),
7.16–7.35 (m, 8H), 7.50–7.52 (m, 2H), 10.47 (s, 1H, br). MS (ESI): m=z 251
[M þ Hþ]þ; LC Rt ¼ 1.92 min (10-min method). HRMS calcd. for C16H15N2O
251.11789; found 251.11773.
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