A simple method for the preparation and selective functionalization of 4,5-diaminopyrazoles

Article abstract of DOI:10.1016/S0040-4039(03)00398-8

A simple procedure for the synthesis and further functionalization of 4,5-diaminopyrazoles using mild conditions is reported herein. The desired products were obtained in good yield, and the structures have been confirmed by X-ray crystallography.

Full text of DOI:10.1016/S0040-4039(03)00398-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3009–3011
A simple method for the preparation and selective
functionalization of 4,5-diaminopyrazoles
Benjamin E. Blass,a,* Anil Srivastava,b Keith R. Coburn,a Amy L. Faulknera and William L. Seibela
aProcter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason Montgomery Road, Mason, OH 45040, USA
bChembiotek Research International, Salt Lake, Block BN, Sector V, Kolkata-700091, India
Received 13 January 2003; revised 4 February 2003; accepted 4 February 2003
Abstract—A simple procedure for the synthesis and further functionalization of 4,5-diaminopyrazoles using mild conditions is
reported herein. The desired products were obtained in good yield, and the structures have been confirmed by X-ray
crystallography. © 2003 Published by Elsevier Science Ltd.
Aromatic amines, particularly diamines, are widely
used as intermediates in the preparation of important
materials such as pharmaceuticals, agricultural chemi-
cals, and dyes. We have recently become interested in
4,5-diaminopyrazoles, as they, and their derivatives,
have been shown to possess a wide range of interesting
biological properties including PAF-antagonism, anti-
cancer, anti-HIV, antiasthmatic and anti-inflammatory
activity.1 Various 4,5-diaminopyrazole derivatives have
been reported as intermediates in the preparation of
1,2,4-triazoles2, imidazo[4,5-c]pyrazoles3, and benzo-
diazepines4, an important class of psychotherapeutic
compounds. In addition, this class of compounds has
found wide use in the hair dye industry.5 There have
been a limited number of synthetic approaches to 4,5-
diaminopyrazoles reported in the literature, including
preparation from azopyrazole with the application of
sodium dithionite.6 Palladium catalyzed reduction of
nitrosopyrazole derivatives with both hydrazine and
hydrogen has also been reported.7
sion to 5-amino-4-pyrazolyl ureas. Thus, commercially
available 5-aminopyrazoles (1a–e) were oxidized with
sodium nitrite in the presence of dilute hydrochloric
acid at 0°C, and the resulting nitroso intermediates
were subsequently reduced in situ with stannous chlo-
ride dihydrate to provide the desired 4,5-diaminopyra-
zoles in fair to excellent yield (2a–e, Scheme 1, Table 1).
Further functionalization of 2a–e was then easily
accomplished by condensation with an isocyanate in
ethanol to provide the corresponding urea derivative 3
(Table 2). Surprisingly, the reactions were highly selec-
tive, as only one of the two possible urea regioisomers
Table 1. Formation of 4,5-diaminopyrazoles8
Entry
R1
R2
Yield (%)
2a
2b
2c
2d
2e
Ph
p-Tolyl
Ph
Me
Me
Me
t-Butyl
Ph
Ph
Me
90
94
50
86
50
We wish to report a mild procedure for the synthesis of
various 4,5-diaminopyrazoles and their simple conver-
Scheme 1.
Keywords: 4,5-diaminopyrazoles; nitrosation; urea derivatives.
* Corresponding author. Fax: 513-622-3797; e-mail: blass.be@pg.com; anil@chembiotek.com
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0040-4039(03)00398-8

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B. E. Blass et al. / Tetrahedron Letters 44 (2003) 3009–3011
Table 2. Functionalization of 4,5-diaminopyrazoles9
istry, Turin, Italy, 23–26 September 1997; (d) Namiki, T.;
Yuasa, M.; Takakuwa, T.; Ichinomiya, S.; Kawasu, Y.;
Kishii, K. WO9833799 A1, 1998.
2. Moderhack, D. Liebigs Ann. 1996, 777–779.
3. Vicentini, C. B.; Veronese, A. C.; Giori, M. G. Tetra-
hedron Lett. 1998, 29, 6171–6172.
4. Braulio, I. O.; Henry, I. I.; Jairo, Q. P. J. Heterocyclic
Chem. 1999, 36, 635–638.
5. (a) Goettel, O.; Pirrello, A.; Hayoz, A.; Morand, E. EP
1236460 A1, 2002; (b) Braun, H. J. DE 19643059 A1,
1998; (c) Malle, G.; Vidal, L.; Samain, H. EP 796850 A1,
1997; (d) Weinges, A.; Balzer, W. R.; Gerstung, S.; Ger-
stung, S. D. DE 4422603 A1, 1996; (e) Jean, C. WO
0251373 A1, 2002; (f) Javet, M.; Dousse, C.; Le, C. D. DE
10109806 A1, 2002.
Figure 1. X-Ray crystal structure of 3a.
was observed. Condensation of the isocyanate with the
4-amino group dominates the reaction as indicated by
X-ray crystal structure, Figure 1. This is most likely due
to the decreased nucleophilicity of the 5-amino sub-
stituent of the amino pyrazole.
6. Eid, E. E.; Bonner, T. G.; Lewis, D. J. Heterocyclic Chem.
1983, 20, 1501–1503.
7. (a) Vicentini, C. B.; Ferretti, V.; Veronese, A. C.;
Guarneri, M.; Manfrini, M.; Giori, P. Heterocycles 1995,
41, 497–506; (b) Fray, M.; Bull, D. J.; Kinns, M. J. Chem.
Res. Synop. 1992, 1, 10–11.
In summary, we have developed an efficient and simple
procedure for the preparation of 4,5-diaminopyrazoles
and their selective conversion to the corresponding
mono-urea derivatives in good yield.
8. Typical procedure (2b): A solution of NaNO2 (260 mg,
3.77 mmol) in water (2.5 mL) was added drop wise to a
solution of 5-amino-3-tert-butyl-1-p-tolyl pyrazole (HCl
salt, 1.0 g, 3.77 mmol) in aqueous 0.8 N HCl (50 mL) at
0°C. The solution was stirred at 0°C for 10 minutes and
then a solution of stannous chloride dihydrate (3.40 g, 15.1
mmol) in conc. HCl (20 mL) was added slowly. The
resultant reaction mixture was allowed to warm slowly to
room temperature and stirred for 15 minutes. The solution
was then basified with NaOH and extracted with EtOAc
References
1. (a) Fray, M. J.; Bull, D. J.; Cooper, K.; Parry, M. J.;
Stefaniak, M. H. J. Med. Chem. 1995, 38, 3524–3535; (b)
Makarov, Y. 14th International Symposium on Medicinal
Chemistry, Maastricht, The Netherlands, 8–12 September
1996; (c) Daidone, G.; Maggio, B.; Raffa, D.; Plescia, S.
Schillaci 1st Italian–Swiss Meeting on Medicinal Chem-

B. E. Blass et al. / Tetrahedron Letters 44 (2003) 3009–3011
3011
(3×100 mL). The combined extracts were dried over anhy-
drous Na2SO4. Removal of the solvent in vacuo gave the
desired product 2b (868 mg, 94%). The product obtained
could be carried to the next step without purification.
Spectral data for Table 1. Entry 2a (1H NMR, 300 MHz,
CDCl3): l 2.23 (s, 3H), 7.42–7.58 (m, 5H). (M+H) 189.
Entry 2b (1H NMR, 300 MHz, CDCl3): l 1.34 (s, 9H),
2.31 (s, 3H), 7.26–7.46 (m, 4H). (M+H) 245. Entry 2c (1H
NMR, 300 MHz, CDCl3): l 7.55–7.72 (m, 6H), 7.81 (d,
J=7.30 Hz, 2H), 7.98 (d, J=7.10 Hz, 2H). (M+H) 251.
Entry 2d (1H NMR, 300 MHz, CDCl3): l 3.63 (s, 3H),
7.27 (m, 2H), 7.37 (t, J=5.5 Hz, 1H), 7.68 (d, J=7.0 Hz,
2H). (M+H) 189. Entry 2e (1H NMR, 300 MHz, CDCl3):
l 2.21 (s, 3H), 3.71 (s, 3H). (M+H) 127.
J=5.5 Hz each, 2H), 3.71 (s, 3H), 4.65 (br s, 1H), 7.12 (d,
J=6.67 Hz, 2H), 7.38–7.50 (m, 8H). (M+H) 394. Entry 3d
(1H NMR, 300 MHz, CDCl3): d 0.95 (t, J=7.20 Hz, 3H),
1.29 (m, 2H), 1.45 (m, 2H), 2.23 (s, 3H), 3.17 (t, J=7.0
Hz, 2H), 7.50–7.62 (m, 5H). (M+H) 288. Entry 3e (1H
NMR, 300 MHz, CDCl3): l 1.11 (s, 9H), 2.21 (s, 3H), 3.71
(s, 3H), 3.84 (dd, J=3.0 Hz each, 2H), 4.52 (br s, 1H),
7.44–7.56 (m, 5H). (M+H) 390. Entry 3f (1H NMR, 300
MHz, CDCl3): l 1.28 (t, J=7.13 Hz, 3H), 2.09 (s, 3H),
2.21 (s, 3H), 2.54 (m, 2H), 2.73 (m, 2H), 4.15 (q, J=7.0
Hz, 2H), 4.49 (m, 1H), 7.34–7.53 (m, 5H). (M+H) 392.
Entry 3g (1H NMR, 300 MHz, CDCl3): l 1.13 (m, 3H),
1.23 (s, 9H), 1.92 (s, 3H), 1.98 (m, 2H), 2.26 (s, 3H), 2.37
(m, 2H), 4.06 (m, 2H), 4.45 (m, 1H), 7.10–7.30 (m, 4H).
(M+H) 448. Entry 3h (1H NMR, 300 MHz, MeOD): l 1.42
(s, 9H), 2.46 (s, 3H), 3.76 (s, 3H), 6.83–6.90 (m, 2H),
7.29–7.35 (m, 6H). (M+H) 394. Entry 3i (1H NMR, 300
MHz, MeOD): l 2.47 (s, 3H), 7.15–7.50 (m, 11H), 7.60 (d,
J=7.87 Hz, 1H), 7.68 (t, J=6.55 Hz, 1H), 7.90 (s, 1H).
(M+H) 412. Entry 3j (1H NMR, 300 MHz, MeOD): l 1.27
(t, J=7.13 Hz, 3H), 2.05 (s, 3H), 2.12 (m, 2H), 2.48 (m,
2H), 3.72 (s, 3H), 4.20 (q, J=7.12 Hz, 2H), 4.30 (t,
J=2.20 Hz, 1H), 7.36–7.53 (m, 5H). (M+H) 392. Entry 3k
(1H NMR, 300 MHz, MeOD): l 0.96 (t, J=7.30 Hz, 3H),
1.35 (m, 2H), 1.56 (m, 2H), 2.30 (s, 3H), 3.19 (t, J=7.0
Hz, 2H), 3.73 (s, 3H). (M+H) 226.
9. Typical procedure (3a): 4,5-Diamino-3-methyl-1-phenyl
pyrazole 2a (100 mg, 0.53 mmol) was dissolved in EtOH
(20 mL) followed by the addition of phenyl isocyanate
(63.13 mg, 0.53 mmol). The resulting reaction mixture was
stirred at room temperature for 2 hours. Solvent was
evaporated and the crude residue was purified over prepar-
ative HPLC affording 3a in 50% yield (Rf 0.30, 5%
MeOH-DCM). Spectral data for Table 2. Entry 3a (1H
NMR, 300 MHz, CDCl3): l 2.60 (s, 3H), 6.80–7.55 (m,
10H). (M+H) 308. Entry 3b (1H NMR, 300 MHz, CDCl3):
l 2.31 (s, 3H), 3.79 (s, 3H), 6.83 (d, J=8.5 Hz, 2H), 7.23
(d, J=8.5 Hz, 2H), 7.50–7.60 (m, 5H). (M+H) 338. Entry
3c (1H NMR, 300 MHz, CDCl3): l 2.10 (s, 3H), 3.13 (dd,