Novel synthesis of 5-amino-3-bromo-1-(tert-butyl)-1H-pyrazole-4- carbonitrile: A versatile intermediate for the preparation of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides

Article abstract of DOI:10.1021/ol301655f

A simple, novel, and efficient route for the synthesis of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides 1 has been devised. Preparation of pyrazole bromide 3 from potassium tricyanomethanide can be accomplished in only two steps in good yield a

Full text of DOI:10.1021/ol301655f

ORGANIC
LETTERS
2012
Vol. 14, No. 15
3906–3908
Novel Synthesis of 5-Amino-3-bromo-
1-(tert-butyl)-1H-pyrazole-4-carbonitrile: A
Versatile Intermediate for the Preparation
of 5-Amino-3-aryl-1-(tert-butyl)-1H-
pyrazole-4-carboxamides
Mark A. Bobko, Arun C. Kaura, Karen A. Evans,* and Dai-Shi Su
GlaxoSmithKline, Cancer Research, Protein Dynamics Discovery Performance Unit,
1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States
Karen.a.evans@gsk.com
Received June 15, 2012
ABSTRACT
A simple, novel, and efficient route for the synthesis of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-carboxamides 1 has been devised. Preparation
of pyrazole bromide 3 from potassium tricyanomethanide can be accomplished in only two steps in good yield and features a selective Sandmeyer
reaction on the corresponding diaminopyrazole. This allows for a more versatile synthesis of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-
carboxamides 1 than was previously possible.
Pyrazole1 is an extensively utilized moiety, particularly
in the field of medicinal chemistry, both as a pendant
functional group and as a core template in a wide variety
of therapeutic areas.2 During the course of a medicinal
chemistry campaign, a highly efficient and convergent
synthesis of 5-amino-3-substituted-1-(tert-butyl)-1H-pyr-
azole-4-carboxamides 1 was desired in order to rapidly
access analogues at the 3-position (Figure 1). Our investi-
gations into the literature revealed two main approaches to
the synthesis of 5-amino-3-substituted-1-(tert-butyl)-1H-
pyrazole-4-carboxamides 1. The first involves converting
an acid chloride to 2-(methoxyarylmethylene)malononitrile
(4), followed by ring closure with tert-butyl hydrazine, to
afford the pyrazole 5 (Scheme 1).3 While the first two steps
are high yielding and robust, subsequent hydrolysis of the
cyano group with sodium hydroxide, hydrogen peroxide,
and tetrabutylammonium hydrogensulfate (TBAHS) to
form carboxamide 1 is highly variable (15À75% reported
yield). To address this liability, an alternate approach in
which the carboxamide functionality can be incorporated
into compound 6 prior to the pyrazole ring formation
(Scheme 1) has been utilized.4,5 This approach is more
labor intensive. Additionally, both approaches require
that each 3-aryl analogue be individually prepared in a
linear fashion from the corresponding aryl acid chloride.
We now report the development and application of an
efficient three-step route to produce bromocarboxamide 2
that allows for a more versatile synthesis of various
(1) For recent reviews on the synthesis of pyrazoles, see: (a) Fustero,
S.; Sanchez-Rosello, M.; Barrio, P.; Simon-Fuentes, A. Chem. Rev.
2011, 111, 6984–7034. (b) Yoon, J.-Y.; Lee, S.; Shin, H. Curr. Org. Chem.
2011, 15, 657–674. (c) Fustero, S.; Simon-Fuentes, A.; Sanz-Cervera,
J. F. Org. Prep. Proced. Int. 2009, 41, 253–290.
(2) For recent reviews on pyrazoles in medicinal chemistry, see: (a)
Keter, F. K.; Darkwa, J. Biometals 2012, 25, 9–21. (b) Tambe, S. K.;
Dighe, N. S.; Pattan, S. R.; Kedar, M. S.; Musmade, D. S. Pharmaco-
logyonline 2010, 2, 5–16. (c) Elguero, J.; Goya, P.; Jagerovic, N.; Silva,
A. M. S. Targets in Heterocycl. Syst. 2002, 6, 52–98.
(3) Adams, J. L.; Kasparec, J.; Silva, D. WO 03072541 A2,
September 4, 2003.
(4) Davis, P. D.; Davis, J. M.; Moffat, D. F. C. WO 9740019 A1,
October 30, 1997.
(5) Tominaga, Y.; Matsuoka, Y.; Oniyama, Y.; Uchimura, Y.;
Komiya, H.; Hirayama, M.; Kohra, S.; Hosomi, A. J. Heterocyl. Chem.
1990, 27, 647–660.
r
10.1021/ol301655f
Published on Web 07/18/2012
2012 American Chemical Society

5-amino-3-substituted-1-(tert-butyl)-1H-pyrazole-4-carbox-
amides 1 than was previously possible.
low yield (<5%) (Scheme 3).8 While this method was
reported to provide the corresponding N-1-methyl and
N-1-unsubstituted compounds in high yields (>80% re-
ported yield), the use of this reaction was impractical for
generating preparative quantities of the N-1-tert-butyl
intermediate 10.
Scheme 1. Synthesis of 5-Amino-3-substituted-1-(tert-butyl)-
1H-pyrazole-4-carboxamides from Acid Chlorides
Scheme 3. Synthesis of 3,5-Diamino-1-(tert-butyl)-1H-pyra-
zole-4-carbonitrile (10) from Malononitrile Derivative 9
Potassium tricyanomethanide (11) has been reported in
the literature for the successful preparation of N-1-methyl-
3,5-diamino-4-cyanopyrazole (13).9 We hypothesized that
this same reagent could also be used to form the desired
tert-butyl intermediate 10. Gratifyingly, treatment of po-
tassium tricyanomethanide (11) with tert-butylhydrazine
afforded 3,5-diamino-1-(tert-butyl)-1H-pyrazole-4-carbo-
nitrile (10) in 41% isolated yield on a multigram scale.
Similarly, this method was applied to the synthesis of N-1-
iso-propyl intermediate 12and N-1-methyl intermediate 13
in 48% and 49% yields, respectively (Scheme 4).
Figure 1. Retrosynthesis of 5-amino-3-substituted-1-(tert-butyl)-
1H-pyrazole-4-carboxamides 1 from 5-amino-3-bromo-1-(tert-
butyl)-1H-pyrazole-4-carbonitrile (3).
Our proposal was to efficiently prepare the bromo-
intermediate 2 on scale which would enable the installation
of a C-3 aryl group as the last step in the synthesis.
Retrosynthetically, compound 2 would then be derived
from compound 3 (Figure 1). Attempted bromination of
1-tert-butyl pyrazole6 7 resulted exclusively in the forma-
tion of diazenyl byproduct 8 instead of the desired bromide
3, which was undetectable (Scheme 2).7
Scheme 4. Synthesis of 5-Amino-3-substituted-1-(tert-butyl)-
1H-pyrazole-4-carboxamides 1 from Potassium
Tricyanomethanide (11)
Scheme 2. Attempted Bromination of 5-Amino-1-(tert-butyl)-
1H-pyrazole-4-carbonitrile (7)
With the desired 3,5-diamino-pyrazole 10 (R = tBu) in
hand, we carried out the proposed Sandmeyer reaction.
We hypothesized that the 3-bromo regioisomer would be
afforded as the major product due to the steric hindrance
adjacent to the 5-amino group. Indeed, the Sandmeyer
reaction afforded 3 selectively in 59% yield (Scheme 4).
Similarly, when the pyrazole N-1 nitrogen was substituted
with iso-propyl (12) the Sandmeyer reaction was regiose-
lective for the 3-amino group and afforded the 3-bromo
regioisomer 14 as the major product. Excellent selectivity
We postulated that the bromo intermediate 3 could
instead be formed from diaminopyrazole 10 via a selective
Sandmeyer reaction. The key intermediate 10 could be
synthesized from malononitrile derivative 9, but in very
(6) Prepared according to the method described in: Bulawa, C. E.;
Devit, M.; Elbaum, D. WO 2009062118 A2, May 14, 2009.
(7) Salaheldin, A. M.; Oliveira-Campos, A. M. F.; Rodrigues, L. M.
Tetrahedron Lett. 2007, 48, 8819–8822.
(8) Ried, W.; Aboul-Fetouh, S. Tetrahedron 1988, 44, 7155–7162.
(9) Percival, A.; Judson, P. N. U.S. Patent 4,163,846, August 7,
1979.
Org. Lett., Vol. 14, No. 15, 2012
3907

Hydrolysis of the cyano group proceeded cleanly to
provide the carboxamide 2 in 79% yield. 5-Amino-3-
bromo-1-(tert-butyl)-1H-pyrazole-4-carboxamide (2) was
then coupled successfully with the corresponding boro-
nates or boronic acids 16aÀe via SuzukiÀMiyaura reac-
tion under microwave heating. The desired 3-aryl and
3-heteroaryl substituted pyrazoles 1aÀe were formed in
generally good yields (31À87%, Table 1). The tert-butoxy
carbonyl (tBoc) indole protecting group was removed
in situ under the SuzukiÀMiyaura reaction conditions
(entries 2, 3).
Table 1. Examples of SuzukiÀMiyaura Cross-Coupling of
Bromopyrazole 2 with Boronates 16aÀea
In summary, a simple, novel, and efficient route for the
synthesis of 5-amino-3-aryl-1-(tert-butyl)-1H-pyrazole-4-
carboxamides 1 was developed. Preparation of the pre-
viously unknown pyrazole bromide 3 from potassium
tricyanomethanide (11) can be accomplished in only two
steps in good yield and features a selective Sandmeyer
reaction on diaminopyrazole 10. The synthesis is also
scalable and requires only a single chromatographic pur-
ification. Importantly, C-3 can conveniently be diversified
in the final step. The chemistry illustrated here provides a
new route by which numerous and diverse medicinally
useful pyrazole compounds can be readily accessed.
Acknowledgment. The authors thank Seth Grant
(GlaxoSmithKline, Cancer Research, Protein Dynamics
Medicinal Chemistry) as well as Beth Knapp-Reed
and Mark Elban (GlaxoSmithKline, Computational and
Structural Chemistry) for helpful discussions and Minghui
Wang (GlaxoSmithKline, Analytical Chemistry) for assis-
tance with NMR spectra.
a All reaction used 1 equiv of pyrazole bromide 2 and 1.0À1.1 equiv
of aryl boronate 16, on 100À150 mg scale.
Supporting Information Available. Full experimental
procedures and characterization for all new compounds.
This material is available free of charge via the Internet
at http://pubs.acs.org.
was also observed in the formation of the N-1 methyl
derivative 15. The 5-bromo regioisomer was not observed
in all the substrates studied.
The authors declare no competing financial interest.
3908
Org. Lett., Vol. 14, No. 15, 2012