A novel route to 4-aminopyrazoles and aminopyrazolo[4,3-b]pyridines

Article abstract of DOI:10.1515/znb-2006-0917

3-Oxo-2-arylhydrazononitriles 6 are readily converted into 4-aminopyrazoles 1 via reaction with α-haloketones, chloroacetonitrile and ethyl chloroacetate. The aminopyrazoles are readily converted into arninopyrazolo[4,3-b]pyridines upon treatment with mal

Full text of DOI:10.1515/znb-2006-0917

A Novel Route to 4-Aminopyrazoles and Aminopyrazolo[4,3-b]pyridines
Abdellatif M. Salaheldin, Tayseer A. Abdallah, Naglaa F. Radwan, and
Hamdi M. Hassaneen
Department of Chemistry, Faculty of Science, Cairo University, Giza, A. R. Egypt
Reprint requests to Dr. A. M. Salaheldin. E-mail: amsalaheldin@yahoo.com
Z. Naturforsch. 61b, 1158 – 1161 (2006); received January 9, 2006
3-Oxo-2-arylhydrazononitriles 6 are readily converted into 4-aminopyrazoles 1 via reaction with
α-haloketones, chloroacetonitrile and ethyl chloroacetate. The aminopyrazoles are readily converted
into aminopyrazolo[4,3-b]pyridines upon treatment with malononitrile. Compounds are readily dia-
zotized to yield unstable diazonium salts that readily cyclized into pyrazolo[4,3-c]pyridazines.
Key words: 2-Arylhydrazononitriles, Aminopyrazoles, α-Haloketones,
Aminopyrazolo[4,3-b]pyridines, Pyrazolo[4,3-c]pyridazine
Introduction
Similar to its behavior toward chloroacetonitrile,
compound 6 also reacted with ethyl chloroacetate and
with chloroacetone to yield 1b, c, respectively, in good
yields.
We have investigated the possible utility of com-
pound 1 as precursors to pyrazoloazines. It was found
that compound 1a reacted with malononitrile in reflux-
ing ethanol and in the presence of piperidine to yield
the pyrazolo[4,3-b]pyridine derivative 9 (Scheme 2).
Initial formation of 8 seems most likely; however, at-
tempted isolation of 8 failed. Clearly, the aromaticity
of the cyclization product is a driving force for the im-
mediate formation of 9.
Diazotization of 1 afforded unstable diazonium salts
10 that readily cyclized into pyrazolo[4,3-c]pyridazine
11. Acetylation of compound 1 in acetic anhydride af-
forded 13 in excellent yield. The IR spectrum of com-
pound 15 shows absorptions of two carbonyl group at
1710 and 1673, a cyano group at 2230 and a NH group
at 3337 cm−1. The 1H NMR spectrum reveals two CH3
groups at δ = 2.10 and 2.58 ppm which indicates that
no further cyclization has occurred.
The synthesis of 4-aminopyrazole-5-carboxylates
1 is now receiving considerable interest [1 – 4] as
these compounds are important precursors to important
pharmaceuticals among which Viagra (2) and allopuri-
nal (3) are two well-known compounds [5 – 8]. More-
over, 4-aminopyrazolescan also be considered as inter-
esting precursors to dyes. 4-Derivatives of 1 are gener-
ally prepared via nitration of pyrazole 4 and reduction
of formed nitro derivatives 5 [9]. This approach is both
multistageous and environmentally non-friendly.
Results and Discussion
In conjunction to our interest in synthesis and reac-
tivity of aminopyrazoles we report a simple and effi-
cient route to 1. Moreover, results of our investigation
on the reactivity of 1 is reported. The work enabled de-
veloping a novel efficient route to pyrazolo[4,3-b]pyr-
idines (Scheme 1).
We have found that 6 reacts readily with chloroacet-
onitrile in dioxane in the presence of triethylamine (10
equivalents) to yield products of a molecular formula
corresponding to 7 or isomeric 1a with excellent yield. Experimental Section
Structure 1a was readily established based on 1H NMR
All melting points were measured on a Gallenkamp elec-
data that revealed the absence of a signal for a methyl-
ene function and the appearance of a two-protons D2O-
exchangeable signal at δ = 5.24 ppm for the amino
function. It is assumed that 1a has resulted from in situ
cyclization of initially formed 7. Recently, a similar re-
trothermal melting point apparatus and are uncorrected. IR
spectra were recorded as KBr pellets on a Pye Unicam SP
3-300 Spectrophotometer. 1H and 13C NMR spectra were
recorded in deuterated dimethylsulfoxide [D6]-DMSO or
deutrated chloroform (CDCl3) at 300 MHz on a Varian
sult has been reported with poor to moderate yield [10]. Gemini NMR spectrometer using tetramethylsilane (TMS)
c
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A. M. Salaheldin et al. · A Novel Route to 4-Aminopyrazoles and Aminopyrazolo[4,3-b]pyridines
1159
Scheme 1.
as an internal reference and results are expressed as δ val- 119.75 (C-5), 115.91 (CN), 24.80 (CH3). – MS (EI, 70 eV):
ues. Mass spectra were performed on a Shimadzu GCMS- m/z (%) = 260 (20) [M+]. – C12H9ON4Cl (260.6): calcd.
QP 1000 Ex mass spectrometer at 70 eV. Elemental analyses C 55.29, H 3.48, N 21.49, Cl 13.60; found C 55.10, H 3.60,
were carried out at the Microanalytical Center of Cairo Uni- N 21.30, Cl 13.50.
versity. The azo derivatives 6a, b were prepared as previously
reported in the literature [11].
Ethyl 3-acetyl-4-amino-1-(4-chlorophenyl)-1H-pyrazole-5-
carboxylate (1b)
General procedure for the preparation of compounds 1a−c
M. p. 143 ◦C. Yield: 75 %. – IR: ν = 3492, 3380 (NH2),
To a solution of 6b (2.21 g, 0.01 mol) in dioxane (25 ml) 1711, 1672 (CO) cm−1. – 1H NMR (300 MHz, [D6]-
and triethylamine (10.1 g, 0.1 mol) chloroacetonitrile, ethyl DMSO): δ = 1.23 (t, 3H, J = 7.2 Hz, CH3), 2.60 (s, 3H,
chloroacetate or chloroacetone (1 ml, 0.016 mol) was added. CH3), 4.21 (q, 2H, J = 7.2 Hz, CH2), 5.78 (s, 2H, NH2), 7.29
The reaction mixture was refluxed for 3 h, then evaporated in (d, 2H, J = 12 Hz, 2H Ar), 7.35 (d, 2H, J = 12 Hz, 2H Ar). –
vacuo, and the solid product was filtered off and crystallized MS (EI, 70 eV): m/z (%) = 307 (27) [M+]. – C14H14O3N3Cl
from ethanol.
(307.7): calcd. C 54.64, H 4.59, N 13.65, Cl 11.52; found
C 54.60, H 4.40, N 13.70, Cl 11.60.
3-Acetyl-4-amino-1-(4-chlorophenyl)-1H-pyrazole-5-carb-
onitrile (1a)
1-[5-Acetyl-4-amino-2-(4-chlorophenyl)-2H-pyrazol-3-yl]-
ethanone (1c)
◦
M. p. 156 C. Yield: 85%. – IR: ν = 3451, 3348 (NH2);
1
◦
M. p. 138 C. Yield: 72%. – IR: ν = 3445, 3350 (NH2),
2217 (CN), 1671 (CO) cm−1. – H NMR (300 MHz, [D6]-
DMSO): δ = 2.61 (s, 3H, CH3), 5.24 (s, 2H, NH2), 7.50 1678, 1669 (CO) cm−1. – 1H NMR (300 MHz, [D6]-
(d, 2H, J = 12 Hz, 2H Ar), 7.69 (d, 2H, J = 12 Hz, 2H DMSO): δ = 2.55 (s, 3H, CH3), 2.61 (s, 3H, CH3), 6.31
Ar). – 13C NMR (75 MHz, [D6]-DMSO): δ = 197.91 (CO), (s, 2H, NH2), 7.39 (d, 2H, J = 12 Hz, 2H Ar), 7.52 (d, 2H,
139.03 (C-3), 137.62, 135.94 (C-4), 134.62, 128.81, 122.23, J = 12 Hz, 2H Ar). – MS (EI, 70 eV): m/z (%) = 277 (18)
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A. M. Salaheldin et al. · A Novel Route to 4-Aminopyrazoles and Aminopyrazolo[4,3-b]pyridines
Scheme 2.
[M+]. – C13H12O2N3Cl (277.7): calcd. C 56.22, H 4.36, cm−1. – 1H NMR (300 MHz, [D6]-DMSO): δ = 1.15 (t,
N 15.13, Cl 12.77; found C 56.10, H 4.35, N 15.20, Cl 12.80. 3H, J = 7.5 Hz, CH3), 4.32 (q, 2H, CH2), 7.40 (d, 2H,
J = 12 Hz, 2H Ar), 7.66 (d, 2H, J = 12 Hz, 2H Ar), 7.76 (s,
1H), 13.30 (s, 1H, OH). – 13C NMR (75 MHz, [D6]-DMSO):
δ = 173.40 (CO), 166.52 (C-7), 140.12, 138.38, 136.22
5-Amino-2-(4-chlorophenyl)-7-methyl-2H-pyrazolo[4,3-b]
pyridine-3,6-dicarbonitrile (9)
(C-3), 128.21, 127.24, 120.23, 116.41, 112.60, 108.83, 61.63
(CH2), 12.55 (CH3). – MS (EI, 70 eV): m/z (%) = 318 (31)
[M+]. – C14H11O3N4Cl (318.7): calcd. C 52.76, H 3.48,
N 17.58, Cl 11.12; found C 52.70, H 3.55, N 17.60, Cl 11.10.
A mixture of 1a (2.6 g, 0.01 mol), malononitrile (0.66 g,
0.01 mol) and triethylamine (1.01 g, 0.01 mol) in ethanol
(25 ml) was refluxed for 4 h. The solvent was evaporated
under vacuo, and the crude product was collected and crys-
◦
tallized from ethanol. – M. p. 202 C. Yield: 77%. – IR:
N-[3-Acetyl-1-(4-chlorophenyl)-5-cyano-1H-pyrazol-4-yl]-
acetamide (13)
ν = 3460, 3350 (NH2), 2220, 2215 (CN) cm−1. – 1H NMR
(300 MHz, [D6]-DMSO): δ = 2.48 (s, 3H, CH3), 5.68 (s,
2H, NH2), 7.29 (d, 2H, J = 12 Hz, 2H Ar), 7.45 (d, 2H,
J = 12 Hz, 2H Ar). – 13C NMR (75 MHz, [D6]-DMSO):
δ = 157.05, 148.73, 143.58, 137.91, 134.67, 129.84, 125.30,
124.35, 114.83 (CN), 111.14 (CN), 110.88, 97.95, 15.16
(CH3). – MS (EI, 70 eV): m/z (%) = 308 (22) [M+]. –
C15H9N6Cl (308.7): calcd. C 58.36, H 2.94, N 27.22,
Cl 11.48; found C 58.50, H 3.11, N 27.35, Cl 11.50.
A solution of 1a (2.6 g, 0.01 mol) in acetic anhydride
(25 ml) was refluxed for 3 h. The reaction mixture was cooled
and the solid that separated was collected and crystallized
from ethanol to give 13. – M. p. 195 ◦C; yield: 75%. – IR: ν =
3337 (NH), 2230 (CN), 1707, 1673 (CO) cm−1. – 1H NMR
(300 MHz, [D6]-DMSO): δ = 2.10 (s, 3H, CH3), 2.58 (s,
3H, CH3), 4.45 (s, 1H, NH), 7.22 (d, 2H, J = 10 Hz, 2H Ar),
7.45 (d, 2H, J = 10 Hz, 2H Ar). – 13C NMR (75 MHz, [D6]-
DMSO): δ = 193.60 (CO), 168.23 (CO), 140.84, 136.59,
134.62, 129.79, 128.22, 127.18, 126.03, 110.94 (CN), 27.21
(CH3), 22.84 (CH3). – MS (EI, 70 eV): m/z (%) = 302 (24)
[M+]. – C14H11O2N4Cl (302.7): calcd C 55.55, H 3.66,
N 18.51, Cl 11.71; found C 55.50, H 3.55, N 18.40, Cl 11.80.
Ethyl 2-(4-chlorophenyl)-7-hydroxy-2H-pyrazolo[4,3-c]pyr-
idazine-3-carboxylate (11)
A mixture of 1b (3.07 g, 0.01 mol), sodium nitrite (0.69 g,
0.01 mol) and concentrated hydrochloric acid (2 ml) in acetic
acid (15 ml) was stirred at r. t. for 2 h. The reaction mixture
was poured into ice-water, the product so formed was col-
lected by filtration and crystallized from ethanol to give 11. –
Acknowledgement
The authors are grateful to Prof. M. H. Elnagdi for his sup-
M. p. 210 ◦C. Yield: 72%. – IR: ν = 3421 (OH), 1728 (CO) port, comments and continued help.
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A. M. Salaheldin et al. · A Novel Route to 4-Aminopyrazoles and Aminopyrazolo[4,3-b]pyridines
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[1] J. Quiroga, B. Insusty, S. Gruz, P. Hernandez,
A. Bolanos, R. Moreno, A. Hormaza, J. Heterocyclic
Chem. 35, 333 (1998).
[2] S. M. AL-Mousawi, M. A. Mohammad, M. H. Elnagdi,
J. Heterocyclic Chem. 41, 989 (2001).
[6] K. Unverferth, J. Engel, N. Hoefen, A. Rostock,
R. Guenther, J. Med. Chem. 41, 63 (1988).
[7] K. Harada, S. Nishino, T. Harada, M. Ogami, Jpn.
Tokkyo Koho, JP. 294576, (2001); Chem. Abstr.
135:303884p (2001).
[3] M. H. Elnagdi, N. Al-Awadi, A. W. Erian, in A. R.
Katritizky, C. W. Rees, E. F. Scriven, C. A. Rams-
den (eds): Comprehensive Heterocyclic Chemistry II,
Vol. 7, pp. 431 – 488, Elevier, Amsterdam (1996).
[4] T. M. Elmaati, F. M. El-Taweel, J. Heterocyclic Chem.
41, 109 (2004)
[5] B. E. Blass, A. Sirvastava, K. R. Coburn, A. L.
Faulkner, W. L. Seibel, Tetrahedron Lett. 44, 3009
(2003).
[8] H. Braum, U. S. Pat. Appl. Pupl. US 9044 (2001);
Chem. Abstr. 135:126915b (2001).
[9] H. M. E. Hassaneen, H. M. Hassaneen, M. H. Elnagdi,
Z. Naturforsch. 59b, 1132 (2004).
[10] M. S. T. Goncalves, A. M. F. Oliveira-Campos, L. M.
Rodrigues, M. F. R. P. Proenca, J. Griffiths, H. S. Maia,
M. Kaja, R. Hrdina, J. Chem. Res. 115 (2004).
[11] M. H. Elnagdi, M. M. M. Sallam, H. M. Fahmy,
S. A. M. Ilias, M. A. M. Ibraheim, Helv. Chim. Acta 59,
550 (1976).
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