Convenient synthesis of 4-amino-3,5-disubstituted pyrazoles in one step from the corresponding diketo oximes

Article abstract of DOI:10.1016/j.tetlet.2004.01.045

A convenient one-step protocol for the synthesis of 4-amino-3,5- disubstituted pyrazoles has been developed. This method employs readily available diketo oximes as starting materials, and employs hydrazine hydrate for the cyclization and subsequent reduct

Full text of DOI:10.1016/j.tetlet.2004.01.045

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2137–2139
Convenient synthesis of 4-amino-3,5-disubstituted pyrazoles in
one-step from the corresponding diketo oximes
Tahir Majid, Corey R. Hopkins,* Brian Pedgrift and Nicola Collar
Drug Innovation and Approval, Aventis Pharmaceuticals, Route 202-206, Bridgewater, NJ 08807, USA
Received 7 November 2003; revised 3 December 2003; accepted 12 January 2004
Abstract—A convenient one-step protocol for the synthesis of 4-amino-3,5-disubstituted pyrazoles has been developed. This method
employs readily available diketo oximes as starting materials, and employs hydrazine hydrate for the cyclization and subsequent
reduction of the intermediate nitroso compound.
ꢀ 2004 Elsevier Ltd. All rights reserved.
16
Diketo oximes, 1, find great use in organic synthesis.
These compounds are useful building blocks in five-
membered heterocyclic chemistry. These oximes can be
used for the synthesis of pyrroles,1 thiazoles,2 oxazoles,3
and pyrazoles.4 The pyrazole synthesis is of particular
use because these compounds are themselves building
blocks for larger pyrazole containing structures, such as
sodiumnitrite to a 0 ꢁC solution of 1-benzoylacetone
in AcOH. The diketo oxime was then treated with
hydrazine hydrate in EtOH to yield the nitroso pyrazole
2, which was isolated in excellent yield (97%) after
concentration of the reaction mixture and subsequent
precipitation froman ether/hexanes solution. Reduction
via hydrogenation gave the amino pyrazole 3 (99%). The
procedure worked well and was amenable to scale-up
(10 g scale). However, we were concerned about the
isolation of the nitroso compound 2 owing to the
inherent toxicity of these types of compounds.17 Thus,
we were hoping to avoid an additional reduction step,
thereby removing the need to handle the nitroso com-
pound 2.
pyrazoloisoquinolines,5
pyrazolopyrimidines,6
and
pyrazolopyrazine7 (which find wide use in the pharma-
ceutical industry). There are a number of synthetic
approaches to substituted 4-amino pyrazoles. One such
route uses oximes (such as 1), which when treated with
hydrazine hydrate yield the nitroso pyrazoles, which can
be further reduced under a variety of conditions (H2, Pd/
C;5;8 N2H4, Pd/C, or Raney Ni;9 Na2S2O4;5 SnCl2/
HCl;10 TiO2, irradiation;11 LiAlH4).12 Another approach
is to use a 4-acyl azide pyrazole6 and under Curtius
conditions13 one can obtain the desired 4-amino pyr-
azole. One last example is by nitration of an appropri-
ately substituted pyrazole followed by reduction.14
O
O
aq. NaNO2, AcOH,
O
O
0 oC → rt
96%
N
HO
1
As part of our continuing interest in the synthesis of
novel heterocyclic compounds, we needed an efficient
method for the synthesis of various 4-amino-3,5-disub-
stituted pyrazoles. Our first attempt to synthesize these
compounds followed known literature procedures
starting fromthe readily available b-diketones (Scheme
1).15 The diketo oxime 1 was synthesized in excellent
yield (96%) by addition of an aqueous solution of
N
HN
O
Hydrazine hydrate,
EtOH, 0 oC → rt
N
97%
2
N
HN
H2 (45 psi), EtOH,
10% Pd/C
99%
NH2
Keywords: Pyrazole; Reduction; Hydrazine hydrate.
* Corresponding author. Tel./fax: +1-908-231-3351; e-mail: corey.
hopkins@aventis.com
3
Scheme 1.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.045

2138
T. Majid et al. / Tetrahedron Letters 45 (2004) 2137–2139
Table 1.
O
O
O
O
aq. NaNO2, AcOH,
O
O
0 oC→ rt
N
HN
Hydrazine hydrate,
EtOH, 0 oC → rt
R'
96%
R'
R
R
N
1
HO
N
NH2
HO
Entry
R
R0
Yielda (%)
N
HN
Hydrazine hydrate,
1
2
4-MeOPh
3-ClPh
CH3
CH3
90
86
EtOH, 0 oC → rt
90%
3
2-Furyl
2-Thiophenyl
4-BrPh
CH3
CH3
85
89
NH2
4
3
5
CH3
CH3
95
6
4-(CH3)2NPh
3-(CH3)2NPh
tert-Butyl
Ph
5018
71
Scheme 2.
7
CH3
CH3
8
85
73
9
CH2CH3
To this end, treatment of the diketo oxime 1 with excess
hydrazine hydrate (10 equiv) in EtOH gave the desired
4-amino-3,5-disubstituted pyrazole 3 in excellent yield
(Scheme 2). The reaction worked well with 1-phenyl-
butan-1,3-dione; however, we were interested in a vari-
ety of disubstituted amino pyrazoles and these results
are summarized in Table 1. The examples show that the
reaction is of general utility, and works equally well with
electron-rich aryl groups (entries 1, 6, and 7) and elec-
10
11
12
Ph
3-OBnPh
Ph
CH(CH3)2
CH3
CO2Et
78
84b
48c
a All reactions were run overnight.
b Reaction carried out with 3 equiv of hydrazine hydrate and run for a
total of 40 h.
c Reaction carried out with 2 equiv of hydrazine hydrate and run for
2 h at 45 ꢁC.
tron-deficient groups (entries
2
and 5). The
4-(CH3)2NPh compound (entry 6) gave a lower overall
yield than other compounds investigated due to prob-
lems in the isolation.18 This reaction also allows for the
use of heterocyclic aryl groups (entries 3 and 4) and
alkyl substituents (entry 8). The amount of hydrazine
hydrate needed for this transformation was next evalu-
ated. The reaction can be carried out with only 3 equiv
of hydrazine hydrate; however, the reaction time is
lengthened to 40 h (entry 11).19 The reaction time with
2 equiv of hydrazine hydrate could be shortened by
heating (45 ꢁC), but the yield is lower (entry 12). This
cyclization/reduction reaction is also amenable to scale-
up with this reaction routinely performed on multi-gram
scale.
H
N
H
R2
R2
O
H
NH2
O
N
H2N NH2
N
HO
HO
R2
O
HO
HO
OH
N
R1
HO
N
R1
N
R1
4
H
R2
N
N
HO
H
O
N
R1
-H2O
-H2O
H
H
N
H
N
N
R2
R2
O
R2
HO
N
N
N
H2N NH2
N
R1
N
R1
N
H
R1
NH2
5
N
N
-H2O
7
H2N
6
H
N
H
N
R2
tautomerism
R2
N
R1
N
H
H
N
H2N
R1
N
8
-N2
N
Scheme 3.

T. Majid et al. / Tetrahedron Letters 45 (2004) 2137–2139
2139
3. Abdou, W. M.; El-Khoshnieh, Y. O.; Salem, M. A. I.;
Barghash, R. F. Synlett 2002, 9, 1417.
4. (a) Sachs, A. Chem. Ber. 1907, 40, 668; (b) Cameron, M.;
Gowenlock, B. G.; Boyd, A. S. F. J. Chem. Soc., Perkin.
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5. Cecchi, L.; Colotta, V.; Melani, F.; Palazzino, G.; Filac-
chioni, G.; Martini, C.; Giannaccini, G.; Lucacchini, A.
J. Pharm. Sci. 1989, 78, 437–442.
6. Yuan, J.; Gulianello, M.; De Lombaert, S.; Brodbeck, R.;
Kieltyka, A.; Hodgetts, K. J. Bioorg. Med. Chem. Lett.
2002, 12, 2133–2136.
It appears that the reaction proceeds through the nitroso
pyrazole 5 (by LCMS analysis20) with subsequent
further reduction to the amino pyrazole 8. The initial
cyclization (4 fi 5) usually occurs within 2 h and the
reactions are allowed to proceed overnight to ensure
complete conversion. The reaction is proposed to go
through the mechanism in Scheme 3. After cyclization to
5 hydrazine addition to the aryl nitroso intermediate
gives the hydroxy compound 6. Loss of water and
rearrangement gives the diazo compound 7, which after
loss of N2, yields the amino pyrazole compound 8.
7. Kopp, M.; Lancelot, J.-C.; Dallemagne, P.; Rault, S.
J. Heterocycl. Chem. 2001, 38, 1045.
8. Fray, J. M.; Bull, D. J.; Kinns, M. J. Chem. Res. Miniprint
1992, 1, 227.
Representative example: To a 0 ꢁC solution of 1-(2-
furyl)-butane-1,2,3-trione 2-oxime (4.70 g; 26.0 mmol)
in EtOH (70.0 mL) was added dropwise hydrazine
hydrate (12.0 mL; 6.60 g; 206 mmol). After addition, the
reaction mixture was warmed to rt and allowed to stir
for 16 h, at which point TLC and LCMS showed
essentially complete conversion. The reaction mixture
was concentrated, taken up in EtOAc and washed with
3 N HCl. The organic layer was discarded, and the
aqueous portion basified with 10 N NaOH and then
extracted with EtOAc. The organic extracts were dried
(Na2SO4) and concentrated leaving 3.62 g (22.2 mmol;
85%) of 5-(2-furyl)-3-methyl-1H-pyrazol-4-ylamine as a
tan solid. HPLC RT ¼ 0:45 MS (ESI) 164 (M+H) cal-
9. Pd/C (a) Vincentini, C. B.; Guarneri, M.; Scatturin, A.;
Giori, P.; Heilman, W. Farmaco 1996, 51, 609; (b)
Vincentini, C. B.; Ferretti, V.; Veronese, A. C.; Guarneri,
M.; Manfrini, M.; Giori, P. Heterocycles 1995, 41, 497; (c)
Vincentini, C. B.; Veronese, A. C.; Poli, T.; Guarneri, M.;
Giori, P. Heterocycles 1991, 32, 727; Raney Ni: (d)
Belyaev, E. Yu.; Semina, L. P.; Shpinel, Ya. I. Zh. Org.
Khim. 1973, 9, 273.
10. Aiello, E.; Aiello, S.; Mingoia, F.; Bacchi, A.; Pelizzi, G.;
Musiu, C.; Setzu, M. G.; Pani, A.; La Colla, P.; Marongiu,
M. E. Bioorg. Med. Chem. 2000, 8, 2719.
11. Pace, A.; Buscemi, S.; Vivona, N.; Caronna, T. Hetero-
cycles 2000, 53, 183.
ꢀ
ꢀ
12. Cuadrado, P.; Gonzalez-Nogal, A. M.; Martınez, S.
1
culated for C8H9N3O (163.18); H NMR d 7.46 (d, 1H,
Tetrahedron 1997, 53, 8585.
J ¼ 1:2 Hz), 6.56 (d, 1H, J ¼ 3:1 Hz), 6.49 (dd, 1H,
13. Weinstock, J. J. Org. Chem. 1961, 26, 3511.
14. (a) Baraldi, P. G.; Cacciari, B.; Romagnoli, R.; Spalluto,
G. Synthesis 1999, 453; (b) Evans, G. B.; Furneaux, R. H.;
Gainsford, G. J.; Hanson, J. C.; Kicska, G. A.; Sauve, A.
A.; Schramm, V. L.; Tyler, P. C. J. Med. Chem. 2003, 46,
155.
15. A number of b-diketones are commercially available.
Those diketones that were not commercially available
were synthesized following the procedure of Popic et al.
Popic, V. V.; Korneev, S. M.; Nikolaev, V. A.; Korobit-
syna, I. K. Synthesis 1991, 195–198.
J ¼ 3:3, 1.8 Hz), 2.23 (s, 3H).
In conclusion, we have developed a convenient synthesis
of 4-amino-3,5-disubstituted pyrazoles in one-step from
the corresponding diketo oximes. The reaction has been
shown to work well with a number of substrates
allowing for both aryl and alkyl groups.
16. Saloutin, V. I.; Burgart, Y. V.; Skryabina, Z. E.; Kuzueva,
O. G. J. Fluorine Chem. 1997, 84, 107.
Acknowledgements
17. (a) Koehl, W.; Eisenbrand, G. Toxicology 1999, 743; (b)
New Food Ind. 1978, 20, 20; (c) Coulston, F.; Olajos, E. J.
Ecotoxicol. Environ. Saf. 1982, 6, 89; (d) Nitrosamines
1988, 117.
18. There were numerous uncharacterized side products
formed in the reaction. However, the overall yield of
50% was still an improvement over the two-step protocol
for this compound (40%).
The authors would like to thank Dr. Kent Neuensch-
wander and Mr. Anthony Scotese for their help in
performing some of the experiments included in
this manuscript.
References and notes
19. The nitroso pyrazole compound was formed after 1 h
(TLC and LCMS analysis).
1. (a) Winans, C. F.; Adkins, H. J. Am. Chem. Soc. 1933, 55,
4167; (b) Boiadjiev, S. E.; Lightner, D. A. Tetrahedron
2002, 58, 7411; (c) Boiadjiev, S. E.; Lightner, D. A.
Tetrahedron: Asymmetry 2002, 13, 1721.
2. Yamamoto, H.; Eikyu, T.; Okuda, S.; Kawabata, K.;
Takasugi, H.; Tanaka, H.; Matsumoto, S.; Matsumoto,
Y.; Tawara, S. Bioorg. Med. Chem. 2002, 10, 1535.
20. The LC retention time for the intermediate nitroso
compound of the tandem reaction (1 fi 3) was identical
to 2, which was characterized by LCMS. HPLC (Synergi
2U Hydro-RP 20 · 4.0 mm Col, water (0.1% trifluoroacetic
acid)/acetonitrile (0.1% trifluoroacetic acid) ¼ 10/90 fi 90/
10): Rf ¼ 2:51 min. C10H9N3O (187.20) MS (ESI) 188
(M+H).