New approach to 4- and 5-aminopyrazole derivatives

Article abstract of DOI:10.1080/00397910701557564

3-Oxo-3-(pyrrol-2-yl)-propanenitrile 1 coupled with aromatic diazonium salts to yield the corresponding 2-arylhydrazones 2a-c. The latter products reacted with chloroacetonitrile and ethyl chloroacetate to yield 4-aminopyrazole derivatives 5a-f. Reaction

Full text of DOI:10.1080/00397910701557564

This article was downloaded by: [University of Utah]
On: 25 April 2013, At: 15:00
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
New Approach to 4‐ and 5‐Aminopyrazole
Derivatives
Huwaida M. E. Hassaneen a
a Faculty of Science, Chemistry Department, Cairo University, Giza, Egypt
Version of record first published: 05 Oct 2007.
To cite this article: Huwaida M. E. Hassaneen (2007): New Approach to 4‐ and 5‐Aminopyrazole Derivatives,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
37:20, 3579-3588
To link to this article: http://dx.doi.org/10.1080/00397910701557564
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the
contents will be complete or accurate or up to date. The accuracy of any instructions, formulae,
and drug doses should be independently verified with primary sources. The publisher shall not
be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or
howsoever caused arising directly or indirectly in connection with or arising out of the use of this
material.

Synthetic Communicationsw, 37: 3579–3588, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701557564
New Approach to 4- and 5-Aminopyrazole
Derivatives
Huwaida M. E. Hassaneen
Faculty of Science, Chemistry Department, Cairo University, Giza, Egypt
Abstract: 3-Oxo-3-(pyrrol-2-yl)-propanenitrile 1 coupled with aromatic diazonium
salts to yield the corresponding 2-arylhydrazones 2a–c. The latter products reacted
with chloroacetonitrile and ethyl chloroacetate to yield 4-aminopyrazole derivatives
5a–f. Reaction of 2 with hydrazine hydrate led to formation of 5-amino-4-arylazopyr-
azole 6a–c. Compound 1 reacted also with trichloroacetonitrile to yield enamine 7,
which in turn reacted with hydrazine hydrate to yield 5-amino-3-(pyrrol-2-yl)-
pyrazole-4-carbonitrile 8.
Keywords: 4-amino and 5-aminopyrazoles, dimethylformamide dimethylacetale,
enamine, 3-oxo-3-(pyrrol-2-yl)-propanenitrile
INTRODUCTION
Fused pyrazoles are reported to be biologically interesting compounds. For
example, sildenafil (Viagra), one of the best-known drugs for treatment of
male erection dysfunction, is a pyrazolo[4,3-d]pyrimidine derivative.[1,2]
Allopurinol, still one of the drugs of choice for treatment of gouty arthritis,
is a pyrazolo[3,4-d]pyrimidinone derivative.[3] There are also naturally
occurring antitumor and antibiotical agents formycin A and formycin B.[3]
In addition, Soneta, the best-known drug for treatment of insominia, is a
pyrazolo[1,5-a]pyrimidine derivative.[4] The ring systems are all prepared
from 4- and 5-aminopyrazole carboxylic acid derivatives.[5–7] It is no
wonder that plenty of effort has been made to develop the synthesis of 4- or
5-aminopyrazoles and to provide routes to new aminopyrazole carboxylic
Received in Poland October 4, 2006
Address correspondence to Huwaida M. E. Hassaneen, Faculty of Science,
Chemistry Department, Cairo University, Giza, Egypt. E-mail: huwaidah@hotmail.com
3579

3580
H. M. E. Hassaneen
acid derivatives. However, to my knowledge, 4-aminopyrazole substituted
with pyrrole as ring residue is hitherto unreported.
RESULTS AND DISCUSSION
As a part of our program aimed at developing a synthesis for pyrazoles[8,9] and
condensed pyrazoles,[10] I report here an efficient synthesis for aminopyra-
zoles, which are used as precursors for biologically active fused pyrazoles.
Thus, reacting pyrrole with cyanoacetic acid in acetic anhydride, utilizing a
literature procedure,[11] led to formation of 3-oxo-3-(pyrrol-2-yl)-propaneni-
trile 1 in excellent yield. The latter compound 1 reacted with aromatic
diazonium salts to yield the corresponding arylhydrazones 2a–c in
excellent yields (Scheme 1). The E-structure for hydrazones 2 was preferred
over possible hydrogen-bonded Z-structure 3 based on analog of the
recently reported structure of 3-substituted-2-aryhydrazono-3-oxoalkaneni-
triles, whose E-structure has been confirmed by X-ray crystal structure deter-
mination[12] and supported by theoretical calculation.[13]
Compounds 2 reacted readily with chloroacetonitrile in the presence of
triethylamine to give products of molecular formula corresponding to
structure 5 or its isomeric structure 4 in excellent yield. Structure 5 was
1
readily established based on H NMR data which revealed the absence of a
signal for the methylene group and appearance of two deuterium oxide
exchangeable protons at d 6.58 ppm for the amino group. It is believed that
5a–c has resulted from in situ cyclization of the initially formed 4a–c.
Scheme 1.

4- and 5-Aminopyrazole Derivatives
3581
Similarly, reaction of 2a–c with ethyl chloroacetate afforded 5d–f in
moderate yields. Again 4d–f are assumed to be non isolable intermediates
(Scheme 2). On the other hand, 5-amino-4-arylazo-3-(pyrrol-2-yl)-pyrazoles
6a–c were obtained in excellent yield via reaction of 2a–c with hydrazine
hydrate in refluxing ethanol (Scheme 2).
The reactivity of the methylene group in compound 1 was exploited by
reacting it with trichloroacetonitrile in ethanol in the presence of sodium
acetate to isolate a new enamine 7. The latter compound was used for
synthesis of substituted 5-aminopyrazole 8 by its reaction with hydrazine
hydrate (Scheme 3).
3-Dimethylamino-2-thenoyl-propenenitrile
9
has been reported
recently[14] to afford aminopyrazoles 10 on reaction with hydrazine
hydrate. In my hands, treatment of compound 1 with dimethylformamide
dimethylacetal led to formation of enamine compound 11. Reaction of the
latter enamine with hydrazine hydrate at reflux gave a product whose
structure proved to be pyrazole-4-carbontrile 12 instead of the expected
structure 13 (Scheme 4).
Scheme 2.

3582
H. M. E. Hassaneen
Scheme 3.
EXPERIMENTAL SECTION
All melting points were measured on a Gallenkamp electrothermal melting-
point apparatus and are uncorrected. IR spectra were recorded as KBr
1
pellets on a Pye Unicam SP 3-300 spectrophotometer. H and 13C NMR
spectra were recorded in deuterated dimethylsulfoxide ([2D6]-DMSO) at
300 MHz on a Varian Gemini NMR spectrometer using tetramethylsilane
(TMS) as internal reference, and the results are expressed as d values. Mass
spectra were performed on a Shimadzu GCMS-QP 1000 Ex mass spec-
trometer at 70 eV. Elemental analyses were carried out at the Microanalytical
Center of Cairo University. All reagents and chemicals were obtained from
Aldrich Chemical Company (USA); 3-oxo-3-(pyrrol-2-yl)-propanenitrile 1
was prepared as previously reported in the literature.[11]
General Procedure for the Preparation of Compounds 2a–c
A cold solution of aryldiazonium salt (10 mmol) was prepared by adding a
solution of sodium nitrite (10 mmol in water) to a cold solution of the
aromatic amine hydrochloride (10 mmol) with stirring. The resulting
solution of the diazonium salt was added to a cold solution of compound 1
(1.34 g, 10 mmol) in ethanol (200 ml) containing sodium acetate (10 mmol).
Scheme 4.

4- and 5-Aminopyrazole Derivatives
3583
The reaction mixture was stirred at room temperature for 30 min. The solid
product so formed was collected, washed with water, and crystallized from
dimethylformamide.
Data
3-Oxo-2-(phenyl-hydrazono)-3-(pyrrol-2-yl)-propanenitrile (2a): Yellow
crystals; yield: 1.86 g (78%); mp 2158C. IR (KBr): n ¼ 3365, 3226
(2NH) cm21, 2218 (CN) cm21, 1620 (CO) cm21 1H NMR (300 MHz,
.
DMSO-d6): d ¼ 6.29 (dd, J ¼ 3.8 Hz, 1H, pyrrole-H), 7.17 (d, J ¼ 3.8 Hz,
1H, pyrrole-H), 7.21 (d, J ¼ 2.8 Hz, 1H, pyrrole-H), 7.49–7.55 (m, 5H, Ar-
H), 11.96 (s, 1H, NH), 12.11 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6):
d ¼ 104.77, 113.66, 114.55, 115.30, 121.64, 128.59, 128.72, 130.45,
140.23, 146.96, 185.19 (CO). MS (EI, 70 eV): m/z (%) ¼ 238 (63) [Mþ].
Anal. calcd. for C13H10N4O (238.25): C, 65.54; H, 4.23; N, 23.52. Found:
C, 65.49; H, 4.12; N, 23.48.
2-[(4-Chloro-phenyl)-hydrazono]-3-oxo-3-(pyrrol-2-yl)-propanenitrile (2b):
Dark yellow crystals; yield: 1.99 g (73%); mp 2728C. IR (KBr): n ¼ 3348,
1
3226 (2NH) cm21, 2214 (CN) cm21, 1625 (CO) cm21. H NMR (300 MHz,
DMSO-d6): d ¼ 6.30 (dd, J ¼ 3.8 Hz, 1H, pyrrole-H), 7.16 (d, J ¼ 3.8 Hz, 1H,
pyrrole-H), 7.20 (d, J ¼ 2.8 Hz, 1H, pyrrole-H), 7.46-7.51 (m, 4H, Ar-H),
12.05 (s, 1H, NH), 12.15 (s, 1H, NH). 13C NMR (75 MHz, DMSO-d6):
d ¼ 110.67, 114.66, 117.90, 118.95, 126.24, 128.33, 128.45, 129.51, 141.26,
144.35, 185.19 (CO). MS (EI, 70 eV): m/z (%) ¼ 272 (45) [Mþ]. Anal. calcd.
for C13H9ClN4O (272.70): C, 57.26; H, 3.33; Cl, 13.00; N, 20.55. Found: C,
57.22; H, 3.05; Cl, 12.95; N, 20.48.
2-[(4-Nitro-phenyl)-hydrazono]-3-oxo-3-(pyrrol-2-yl)-propanenitrile (2c):
Reddish brown crystals; yield: 2.20 g (78%); mp 2808C. IR (KBr): n ¼ 3363,
1
3190 (2NH) cm21, 2213 (CN) cm21, 1161 (CO) cm21. H NMR (300 MHz,
DMSO-d6): d ¼ 6.31 (dd, J ¼ 3.8 Hz, 1H, pyrrole-H), 7.22 (d, J ¼ 3.8 Hz,
1H, pyrrole-H), 7.26 (d, J ¼ 2.8 Hz, 1H, pyrrole-H), 7.70 (d, J ¼ 8.6 Hz, 2H,
Ar-H), 8.30 (d, J ¼ 8.6 Hz, 2H, Ar-H), 12.11 (s, 1H, NH), 12.40 (s, 1H, NH).
13C NMR (75 MHz, DMSO-d6): d ¼ 110.80, 113.16, 114.66, 116.52, 121.64,
125.05, 129.72, 138.23, 143.95, 146.87, 187.19 (CO). MS (EI, 70 eV): m/z
(%) ¼ 283 (50) [Mþ]. Anal. calcd. for C13H9N5O3 (283.25): C, 55.13; H,
3.20; N, 24.73. Found: C, 55.05; H, 3.12; N, 24.62.
General Procedure for the Preparation of Compounds 5a–f
To a solution of 2a–c (10 mmol) in triethylamine (10.1 g, 100 mmol), chlor-
oacetonitrile (1.29 g, 16 mmol) or ethyl chloroacetate (2 g, 16 mmol) was
added. The reaction mixture was refluxed for 3 h and then evaporated in

3584
H. M. E. Hassaneen
vacuo, and the solid product was filtered off and crystallized from
dimethylformamide.
Data
4-Amino-1-phenyl-3-(pyrrole-2-carbonyl)-pyrazole-5-carbonitrile (5a):
Pale green crystals; yield: 2.08 g (75%); mp 3208C. IR (KBr): n ¼ 3342,
1
3314, 3210 (NH2, NH) cm21, 2214 (CN) cm21, 1638 (CO) cm21. H NMR
(300 MHz, DMSO-d6): d 6.21 (dd, J ¼ 3.8 Hz, 1H, pyrrole-H), 6.55 (br,
2H, NH2), 7.24 (d, J ¼ 3.8 Hz, 1H, pyrrole-H), 7.44 (d, J ¼ 2.8 Hz, 1H,
pyrrole-H), 7.71–7.84 (m, 5H, Ar-H), 11.95 (br, 1H, NH). 13C NMR
(75 MHz, DMSO-d6): d ¼ 102.65, 105.82, 119.26, 121.66, 124.30, 125.33,
128.23, 129.10, 130.37, 138.95, 142.46, 145.03, 180.47 (CO). MS (EI,
70 eV): m/z (%) ¼ 277 (53) [Mþ]. Anal. calcd. for C15H11N5O (277.29): C,
64.97; H, 4.00; N, 25.26. Found: C, 64.90; H, 3.85; N, 25.45.
4-Amino-1-(4-chloro-phenyl)-3-(pyrrole-2-carbonyl)-pyrazole-5-carboni-
trile (5b): Pale green crystals; yield: 2.4 g (77%); mp 2688C. IR (KBr):
n ¼ 3363, 3320, 3190 (NH2, NH) cm21, 2213 (CN) cm21, 1643 (CO)
cm21
.
1H NMR (300 MHz, DMSO-d6): d ¼ 6.27 (dd, J ¼ 3.8 Hz, 1H,
pyrrole-H), 6.58 (br, 2H, NH2), 7.21 (d, J ¼ 3.8 Hz, 1H, pyrrole-H), 7.54
(d, J ¼ 2.8 Hz, 1H, pyrrole-H), 7.71 (d, J ¼ 8.6 Hz, 2H, Ar-H), 7.85
(d, J ¼ 8.6 Hz, 2H, Ar-H), 12.05 (s, 1H, NH). 13C NMR (75 MHz, DMSO-
d6): d ¼ 102.15, 107.32, 121.33, 122.66, 124.98, 126.06, 128.83, 129.23,
134.70, 136.22, 142.46, 149.29, 179.97(CO). MS (EI, 70 eV): m/z
(%) ¼ 311 (53) [Mþ]. Anal. calcd. for C15H10ClN5O (311.73): C, 57.80; H,
3.23; Cl, 11.37; N, 22.47. Found: C, 57.66; H, 3.16; Cl, 11.28; N, 22.33.
4-Amino-1-(4-nitro-phenyl)-3-(pyrrole-2-carbonyl)-pyrazole-5-carboni-
trile (5c): Dark yellow crystals; yield: 2.44 g (76%); mp 1978C. IR (KBr):
n ¼ 3354, 3319, 3309 (NH2, NH) cm21, 2214 (CN) cm21, 1635 (CO)
cm21
.
1H NMR (300 MHz, DMSO-d6): d ¼ 6.31 (dd, J ¼ 3.8 Hz, 1H,
pyrrole-H), 6.60 (br, 2H, NH2), 7.27 (d, J ¼ 3.8 Hz, 1H, pyrrole-H), 7.66
(d, J ¼ 2.8 Hz, 1H, pyrrole-H), 8.10 (d, J ¼ 8.6 Hz, 2H, Ar-H), 8.48
(d, J ¼ 8.6 Hz, 2H, Ar-H), 12.10 (s, 1H, NH). MS (EI, 70 eV): m/z
(%) ¼ 322 (29) [Mþ]. Anal. calcd. for C15H10N6O3 (322.29): C, 55.90; H,
3.13; N, 26.08. Found: C, 55.77; H, 3.03; N, 25.85.
Ethyl 4-amino-1-phenyl-3-(pyrrole-2-carbonyl)-pyrazole-5-carboxylate
(5d): Yellow crystals; yield: 2.09 g (64%); mp 1558C. IR (KBr): n ¼ 3492,
3380, 3290 (NH2, NH) cm21, 1701, 1642 (2CO) cm21
.
1H NMR
(300 MHz, DMSO-d6): d ¼ 1.24 (t, J ¼ 7.2 Hz, 3H, CH3), 4.42
(q, J ¼ 7.2 Hz, 2H, CH2), 5.82 (br, 2H, NH2), 6.32 (dd, J ¼ 3.8 Hz, 1H,
pyrrole-H), 6.76 (d, J ¼ 3.8 Hz, 1H, pyrrole-H), 7.64 (d, J ¼ 3.5 Hz, 1H,
pyrrole-H), 7.74–7.87 (m, 5H, Ar-H), 11.39 (br., 1H, NH). 13C NMR

4- and 5-Aminopyrazole Derivatives
3585
(75 MHz, DMSO-d6): d ¼ 14.34, 60.92, 105.82, 110.09, 121.66, 124.40,
124.80, 127.55, 129.03, 130.67, 139.79, 142.46, 147.38, 160.11, 180.19
(CO). MS (EI, 70 eV): m/z (%) ¼ 324 (29) [Mþ]. Anal. calcd. for
C17H16N4O3 (324.34): C, 62.95; H, 4.97; N, 17.27. Found: C, 62.80; H,
4.85; N, 17.11.
Ethyl 4-amino-1-(4-chloro-phenyl)-3-(pyrrole-2-carbonyl)-pyrazole-5-
carboxylate (5e): Yellow crystals; yield: 2.29 g (64%); mp 1728C. IR
(KBr): n ¼ 3462, 3383, 3295 (NH2, NH) cm21, 1703, 1632 (2CO) cm21
.
1H NMR (300 MHz, DMSO-d6): d ¼ 1.32 (t, J ¼ 7.2 Hz, 3H, CH3), 4.45
(q, J ¼ 7.2 Hz, 2H, CH2), 5.87 (br, 2H, NH2), 6.30 (dd, J ¼ 3.8 Hz, 1H,
pyrrole-H), 7.29 (d, J ¼ 3.8 Hz, 1H, pyrrole-H), 7.69 (d, J ¼ 2.8 Hz, 1H,
pyrrole-H), 7.78 (d, J ¼ 8.6 Hz 2H, Ar-H), 7.84 (d, J ¼ 8.6 Hz, 2H, Ar-H),
11.25 (br., 1H, NH). 13C NMR (75 MHz, DMSO-d6): d ¼ 14.34, 62.92,
105.82, 110.00, 121.66, 124.80, 125.56, 127.58, 129.93, 132.74, 136.79,
142.46, 143.62, 165.11 (CO), 183.19 (CO). MS (EI, 70 eV): m/z (%) ¼ 358
(56) [Mþ]. Anal. calcd. for C17H15ClN4O3 (358.79): C, 56.91; H, 4.21; Cl,
9.88; N, 15.62. Found: C, 56.82; H, 4.10; Cl, 9.77; N, 15.46.
Ethyl 4-amino-1-(4-nitro-phenyl)-3-(pyrrole-2-carbonyl)-pyrazole-5-car-
boxylate (5f): Dark yellow crystals; yield: 2.43 g (66%); mp 1898C. IR
(KBr): n ¼ 3432, 3370, 3240 (NH2, NH) cm21, 1706, 1646 (2CO) cm21
.
1H NMR (300 MHz, DMSO-d6): d ¼ 1.35 (t, J ¼ 7.2 Hz, 3H, CH3), 4.44
(q, J ¼ 7.2 Hz, 2H, CH2), 5.62 (br, 2H, NH2), 6.33 (dd, J ¼ 3.8 Hz, 1H,
pyrrole-H), 7.26 (d, J ¼ 3.8 Hz, 1H, pyrrole-H), 7.62 (d, J ¼ 2.8 Hz, 1H,
pyrrole-H), 7.80 (d, J ¼ 8.6 Hz, 2H, Ar-H), 7.94 (d, J ¼ 8.6 Hz, 2H, Ar-H),
12.05 (br., 1H, NH). MS (EI, 70 eV): m/z (%) ¼ 369 (47) [Mþ]. Anal.
calcd. for C17H15N5O5 (369.34): C, 55.29; H, 4.09; N, 18.96. Found: C,
55.12; H, 4.02; N, 18.76.
General Procedure for the Preparation of Compounds 6a–c
Hydrazine hydrate (16 mmol) was added to a solution of 2a–c (10 mmol) in
ethanol (25 ml). The reaction mixture was refluxed for 3 h, and then poured
into water. The solid product was filtered off and crystallized from
dimethylformamide.
Data
5-Amino-4-phenylazo-3-(pyrrol-2-yl)-1H-pyrazole (6a): Yellow crystals;
yield: 1.96 g (78%); mp 2288C. IR (KBr): n ¼ 3391, 3250, 3164, 3109
(NH2, 2NH) cm21
.
1H NMR (300 MHz, DMSO-d6): d ¼ 6.15 (dd,
J ¼ 3.8 Hz, 1H, pyrrole-H), 6.84 (d, J ¼ 3.8 Hz, 1H, pyrrole-H), 7.11
(d, J ¼ 2.8 Hz, 1H, pyrrole-H), 7.31–7.50 (m, 5H, Ar-H), 11.05 (br., 2H,

3586
H. M. E. Hassaneen
NH2), 11.85 (br., 1H, NH), 12.25 (br., 1H, NH). MS (EI, 70 eV): m/z
(%) ¼ 252 (100) [Mþ]. Anal. calcd. for C13H12N6 (252.28): C, 61.89; H,
4.79; N, 33.31. Found: C, 61.73; H, 4.62; N, 33.22.
5-Amino-4-(4-chlorophenylazo)-3-(pyrrol-2-yl)-1H-pyrazole (6b): Yellow
crystals; yield: 2.29 g (80%); mp 2848C. IR (KBr): n ¼ 3389, 3262, 3142,
1
3084 (NH2, 2NH) cm21. H NMR (300 MHz, DMSO-d6): d ¼ 6.17 (dd,
J ¼ 3.8 Hz, 1H, pyrrole-H), 6.80 (d, J ¼ 3.8 Hz, 1H, pyrrole-H), 6.91
(d, J ¼ 2.8 Hz, 1H, pyrrole-H), 7.95 (d, J ¼ 8.6 Hz, 2H, Ar-H), 8.32
(d, J ¼ 8.6 Hz 2H, Ar-H), 11.13 (br., 2H, NH2), 11.93 (br., 1H, NH), 12.24
(br., 1H, NH). MS (EI, 70 eV): m/z (%) ¼ 286 (100) [Mþ]. Anal. calcd. for
C13H11ClN6 (286.73): C, 54.46; H, 3.87; Cl, 12.36; N, 29.31. Found: C,
54.36; H, 3.77; Cl, 12.26; N, 29.27.
5-Amino-4-(4-nitrophenylazo)-3-(pyrrol-2-yl)-1H-pyrazole (6c): Red
crystals; yield: 2.34 g (79%); mp 2908C. IR (KBr): n ¼ 3348, 3265, 3191,
1
3112 (2NH, NH2) cm21. H NMR (300 MHz, DMSO-d6): d ¼ 6.15 (dd,
J ¼ 3.8 Hz, 1H, pyrrole-H), 6.75 (d, J ¼ 3.8 Hz, 1H, pyrrole-H), 6.90
(d, J ¼ 2.8 Hz, 1H, pyrrole-H), 7.50 (d, J ¼ 8.6 Hz, 2H, Ar-H), 7.81
(d, J ¼ 8.6 Hz, 2H, Ar-H), 11.03 (br., 2H, NH2), 11.87 (br., 1H, NH), 12.01
(br., 1H, NH). MS (EI, 70 eV): m/z (%) ¼ 297 (100) [Mþ]. Anal. calcd. for
C13H11N7O2 (297.28): C, 52.52; H, 3.73; N, 32.98. Found: C, 52.45; H,
3.62; N, 32.85.
3-Amino-4,4,4-trichloro-2-(pyrrole-2-carbonyl)-but-2-enenitrile (7): To a
solution of 1 (1.34 g, 10 mmol) in ethanol (25 ml) and sodium acetate
(4.1 g, 50 mmol), trichloroacetonitrile (4.33 g, 30 mmol) was added. The
reaction mixture was stirred overnight and then poured into water, and the
solid product was filtered off and crystallized from dimethylformamide to
give 2.28 g (82%) of 7. Mp 1988C. IR (KBr): n ¼ 3399, 3349, 3113 (NH2,
NH) cm21, 2206 (CN) cm21, 1600 (CO) cm21 1H NMR (300 MHz,
.
DMSO-d6): d ¼ 6.23 (dd, J ¼ 3.8 Hz, 1H, pyrrole-H), 7.12 (d, J ¼ 3.8 Hz,
1H, pyrrole-H), 7.39 (d, J ¼ 2.8 Hz, 1H, pyrrole-H), 11.77 (br., 2H, NH2),
12.14 (br., 1H, NH). 13C NMR (75 MHz, DMSO-d6): d ¼ 74.85, 91.45
(CCl3), 110.14, 116.84, 118.87 (CN), 125.63, 127.7, 167.94, 179.40 (CO).
MS (EI, 70 eV): m/z (%) ¼ 277 (25) [Mþ]. Anal. calcd. for C9H6Cl3N3O
(278.53): C, 38.81; H, 2.17; Cl, 38.19; N, 15.09. Found: C, 38.78; H, 2.12;
Cl, 38.02; N, 14.94.
5-Amino-3-(pyrrol-2-yl)-1H-pyrazole-4-carbonitrile (8): To a solution of 7
(2.77 g, 10 mmol) in ethanol (25 ml), hydrazine hydrate (16 mmol) was
added. The reaction mixture was refluxed for 3 h and then poured into
water. The solid product was filtered off and crystallized from ethanol to
give 1.42 g (82%) of 8. Mp 1548C. IR (KBr): n ¼ 3395, 3369, 3206, 3113
(NH2, 2NH) cm21, 2202 (CN) cm21 1H NMR (300 MHz, DMSO-d6):
.
d ¼ 6.20 (dd, J ¼ 3.8 Hz, 1H, pyrrole-H), 7.01 (d, J ¼ 3.8 Hz, 1H, pyrrole-
H), 7.31 (d, J ¼ 2.8 Hz 1H, pyrrole-H), 10.62 (br., 2H, NH2), 11.92 (br.,

4- and 5-Aminopyrazole Derivatives
3587
1H, NH), 12.05 (br., 1H, NH). 13C NMR (75 MHz, DMSO-d6): d ¼ 90.23,
112.62, 116.64, 120.0, 121.84, 127.60, 144.27, 146.82. MS (EI, 70 eV): m/
z (%) ¼ 173 (56) [Mþ]. Anal. calcd. for C8H7N5 (173.18): C, 55.49; H,
4.07; N, 40.44. Found: C, 55.32; H, 3.87; N, 40.24.
3-Dimethylamino-2-(pyrrole-2-carbonyl)-propenenitrile (11): A mixture
of
1
(1.34 g, 10 mmol) and dimethylformamide dimethylacetate
(DMFDMA) (16 mmol) was stirred at rt for 1 h. The solid product was
filtered off and crystallized from ethanol to afford 1.35 g (74%) of 11. Mp
1948C. IR (KBr): n ¼ 3265 (NH) cm21, 2195 (CN) cm21, 1642 (CO)
1
cm21. H NMR (300 MHz, DMSO-d6): d ¼ 3.29 (s, 3H, CH3), 3.37 (s, 3H,
CH3), 6.17 (dd, J ¼ 3.8 Hz, 1H, pyrrole-H), 7.01 (d, J ¼ 3.8 Hz, 1H,
pyrrole-H), 7.21 (d, J ¼ 2.8 Hz, 1H, pyrrole-H), 8.01 (s, 1H), 11.65 (s, 1H,
NH). MS (EI, 70 eV): m/z (%) ¼ 189 (100) [Mþ]. Anal. calcd. for
C10H11N3O (189.22): C, 63.48; H, 5.84; N, 22.21. Found: C, 63.39; H,
5.74; N, 22.15.
3-(Pyrrol-2-yl)-1H-pyrazole-4-carbonitrile (12): A mixture of 11 (1.89 g,
10 mmol) and excess hydrazine hydrate (10 mL) was refluxed for 3 h. The
reaction mixture was poured into water; the product so formed was
collected by filtration and crystallized from ethanol to give 0.95 g (60%) of
12. mp 1288C. IR (KBr): n ¼ 3265, 3119 (2NH), 2213 (CN). 1H NMR
(300 MHz, DMSO-d6): d ¼ 6.12 (dd, J ¼ 3.8 Hz, 1H, pyrrole-H), 6.96
(d, J ¼ 3.8 Hz, 1H, pyrrole-H), 7.22 (d, J ¼ 2.8 Hz, 1H, pyrrole-H), 8.12
(s, 1H), 11.91 (br., 1H, NH), 12.03 (br., 1H, NH). 13C NMR (75 MHz,
DMSO-d6): d ¼ 95.50, 116.47, 117.06, 120.00, 121.85, 128.05, 139.48,
146.92. MS (EI, 70 eV): m/z (%) ¼ 158 (25) [Mþ]. Anal. calcd. for
C8H6N4 (158.16): C, 60.75; H, 3.82; N, 35.42. Found: C, 60.68; H, 3.76; N,
35.36.
REFERENCES
1. Blass, B. E.; Srivastava, A.; Coburn, K. R.; Faulkner, A. L.; Seibel, W. L. A simple
method for the preparation and selective functionalization of 4,5-diamino-
pyrazoles. Tetrahedron Lett. 2003, 44, 3009.
2. Wang, Y.; Wang, J.; Cui, Y.; Fawcett, J.; Gu, J. Liquid chromatographic–tandem
mass spectrometric method for the quantitation of sildenafil in human plasma.
J. Chromatogr. (B) 2005, 828, 118.
3. Elnagdi, M. H.; Al-Awadi, N.; Erian, A. W. Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., and Scriven, E. F. V., Eds.;
Pergamon Press: Oxford, 1996; Vol. 7, pp. 431.
4. Weikel, K. W.; Wickman, I. J. M.; Augustin, S. G.; Strom, J. G. Clinical Thera-
peutics 2000, 22, 11.
5. Salaheldin, A. M.; Abdallah, T. A.; Radwan, N. F.; Hassaneen, H. M. Novel route
to 4-aminopyrazoles and aminopyrazolo[4,3-b]pyridines. Z. Naturforsch. 2006,
16b, 1158.

3588
H. M. E. Hassaneen
6. Abdel-Motaleb, R. M.; Makhloof, A. A.; Ibrahim, H. M.; Elnagdi, M. H. Studies
with 3-functionally substituted 2-arylhydrazononitriles: A new route to 3-substi-
tuted-2-arylhydrazononitriles, 4-amino-pyrazole-5-carbonitriles, azadienes and
cinnolines. J. Heterocycl. Chem. 2006, 43, 931.
7. Burchat, A. F.; Calderwood, D. J.; Friedman, M. M.; Hirst, G. C.; Rafferty, P.;
Ritter, K.; Skinner, B. S. Pyrazolo[3,4-d]pyrimidines containing an extended
3-substituent as potent inhibitors of Lck—a selectivity insight. Bioorg. Med.
Chem. Lett. 2002, 12, 1687.
8. Hassaneen, H. M. E.; Hassaneen, H. M.; Elnagdi, M. H. Enamines in heterocyclic
synthesis: A route to 4-substituted pyrazoles and condensed pyrazoles.
Z. Naturforsch. 2004, 59b, 1132.
9. Al-Saleh, B.; Makhseed, S.; Hassaneen, H. M. E.; Elnagdi, M. H. Studies with
functionally substituted enamines: The reactivity of enaminals and enamino
esters toward naphthoquinone, hydrazonoyl halides, aminoazoles and hippuric
acid. Synthesis 2006, 1, 59.
10. Hassaneen, H. M.; Abdelhadi, H. A.; Abdallah, T. A. Novel synthesis of 1,2,4-
triazolo[4,3-a]pyrimidin-5-one derivatives. Tetrahedron 2001, 57, 10133.
11. Slatt, J.; Romero, I.; Bergman, J. Cyanoacetylation of indoles, pyrroles and
aromatic amines with the combination cyanoacetic acid and acetic anhydride.
Synthesis 2004, 16, 2760.
12. El-Dusouqui, O. M. E.; Abdelkhalik, M. M.; Al-Awadi, N. A.; Dib, H.;
George, B. J.; Elnagdi, M. H. Chemistry of 2-arylhydrazonals: Utility of substi-
tuted 2-arylhydrazono-3-oxoalkanals as precursors for 3-oxoalkanonitriles,
3-amino-isoxazole and 1,2,3- and 1,2,4-triazoles. J. Chem. Res 2006, 291.
13. Kenawi, I. M.; Elnagdi, M. H. DFT and FT-IR analyses of hydrogen bonding in
3-substistuted-3-oxo-arylhydrazonopropanenitriles. Spectrochemica Acta (A)
2006, 65, 805.
14. Gopalasmy, A.; Yang, H.; Ellingboe, J. W.; Tsou, H.; Zhang, N.; Honores, E.;
Powell, D.; Miranda, M.; McGinnis, J. P.; Rabindran, S. K. Pyrazolo[1,5-
a]pyrimidin-7-yl phenyl amides as novel anti-proliferative agents: Parallel
synthesis for lead optimization of amide region. Bioorg. Med. Chem. Lett. 2005,
15, 1591.