Polyfunction al nitriles in organic syntheses: A novel route to aminopyrroles, pyridazines and pyrazolo[3,4-c]pyridazines

Article abstract of DOI:10.3390/molecules14020798

Phenacylmalononitrile 1 reacts with dimethylformamide dimethyl acetal to yield an enaminone which could be readily converted into a pyrrole or an aminopyridazine by treating with ammonium acetate and hydrazine hydrate, respectively. Compound 1 reacted wit

Full text of DOI:10.3390/molecules14020798

Molecules 2009, 14, 798-806; doi:10.3390/molecules14020798
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Polyfunctional Nitriles in Organic Syntheses: A Novel Route to
Aminopyrroles, Pyridazines and Pyrazolo[3,4-c]pyridazines
Saleh M. Al-Mousawi 1,*, Moustafa Sherief Moustafa 1, Herbert Meier 2, Heinz Kolshorn 2 and
Mohamed Hilmy Elnagdi 1
1
Department of Chemistry, Faculty of Science; University of Kuwait: Safat; 13060: Kuwait
2
Institute of Organic Chemistry, Johannes Gutenberg-University, Mainz, Germany
* Author to whom correspondence should be addressed; E-mail: salehalmousawi@hotmail.com;
Tel.: +965-4987081; Fax: +965-4816482.
Received: 8 December 2008; in revised form: 8 January 2009 / Accepted: 10 February 2009 /
Published: 16 February 2009
Abstract: Phenacylmalononitrile 1 reacts with dimethylformamide dimethyl acetal to yield
an enaminone which could be readily converted into a pyrrole or an aminopyridazine by
treating with ammonium acetate and hydrazine hydrate, respectively. Compound 1 reacted
with hydrazine hydrate in ethanol at room temperature to yield the dihydropyridazine 9 as
a single product. In refluxing ethanol this product further reacted with hydrazine hydrate to
yield the novel dihydropyrazolopyridazinamine 10.
Keywords: Aminopyrrole; Pyridazine; Pyrazolopyridazine; Phenacylmalononitrile.
Introduction
Malononitrile and malononitrile derivatives are versatile reagents and their chemistry has been
studied in the past [1-3] and still attracts considerable interest [4-5]. In the past thirty years we have
reported several new approaches to a variety of polyfunctional heterocycles utilizing malononitrile or
substituted malononitriles as precursors [6-10] and several of these products as been established to act
as anti-profiler agents. Very recently we have reported on the utility of benzylmalononitrile as
precursor to diaminopyrazoles, diaminoisoxazoles, thiazoles and condensed azoles [11]. In the present
paper we report the results of our exploration of the synthetic potential of 2-(2-oxo-2-phenylethyl)

Molecules 2009, 14
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malononitrile (1) as a heterocycle precursor. This work has allowed us to develop a new route to
aminopyrroles and aminopyridazines. The amines formed are of potential utility in the dye industry
and as precursors for pharmaceuticals. In addition to that, the reported structures of the reaction
products of (2-oxo-2-phenylethyl) malononitrile (1) with hydrazine hydrate have been reexamined and
corrected in the light of our findings.
Results and Discussion
Phenacylmalononitrile has been prepared by treating malononitrile with phenacyl bromide. While
the literature procedure [12] afforded the desired product in 79 % yield, reaction of phenacyl bromide
with malononitrile in ethanolic potassium hydroxide solution gave 2-(2-oxo-2-phenylethyl)
malononitrile (1) in 85% yield. Heating phenacyl bromide and malononitrile in the presence of
potassium hydroxide solution in a microwave oven at 85 °C gave an 80% yield of the target product.
Reaction of 1 with dimethylformamide dimethyl acetal afforded 2-(3-(dimethylamino)-1-oxo-1-
phenylprop-2-en-2-yl) malononitrile (2) in 75% yield. Although 2 may also exist in the Z form, only 2
(the E form) was isolated according to the NMR NOE difference which indicated that the olefinic
proton at δ = 8.44 ppm is not sterically proximal to the methylene proton at δ = 7.10 ppm. Refluxing 2
in acetic acid in presence of ammonium acetate afforded the aminopyrrole carbonitrile 3 in 60% yield.
On the other hand, reaction of 2 with hydrazine hydrate afforded the aminopyridazine 4 that was
readily oxidized to 5 upon treatment with H2O2 in acetic acid (Scheme 1). It is assumed that initially
ammonia adds across the double bond in 2 to yield an intermediate that then looses dimethylamine or
alternatively, initially losses dimethylamine and then cyclizes to form 4 (Scheme 1).
It has been previously reported by Abdelrazek et al [12] that (2-oxo-2-phenylethyl) malononitrile
(1) reacts with hydrazine hydrate to yield 4-phenacylpyrazole-3,5-diamine (8). Subsequently Elnagdi
et al [13] have shown that the major product of this reaction was in fact the 3-oxo-6-phenyl-2,3,4,5-
tetrahydropyridazine-4-carbonitrile (9). Very recently Abdelrazek [14] claimed that in ethanolic
solution a pyridazineimine was isolated. These should not be possible as water formed during the
reaction would readily hydrolyze readily any imine possibly formed. However, they have also
indicated that in refluxing ethanol other product was formed in less than 35% yield and assumed it to
be 8, reported earlier by Abdelrazek et al. [12]. Now we have found that in ethanol at room
temperature 1 reacts with hydrazine hydrate to yield 9 as sole product in 96 % yield. When 9 was
refluxed in ethanol with hydrazine hydrate a product of molecular formula C11H11N5 (213.2) was
formed. This proved identical with the product obtained by Abdelrazek [12] or the one identified by
Elnagdi et al. [13]. It thus became clear that 8 had never been isolated and that product believed earlier
to be 8 really must have another structure. After inspection of the spectral and analytical data now
wish to assign this product as 5-phenyl-4,7-dihydro-1H-pyrazolo[3,4-c]pyridazin-3-ylamine (10)
obtained by further condensation of dihydropyridazine carbonitrile 9 with hydrazine hydrate (Scheme
2). The NMR data of 10 suggest it is in a fast tautomeric equilibrium with the corresponding 2H
compound.

Molecules 2009, 14
Scheme 1. Syntheses of aminopyridazines and aminopyrrole carbonitrile.
800
O
CN
CN
Ph
H
Me2N
O
O
2A
O
CN
CN
CH2(CN)2
DMFDMA
CH2Br
Ph
Ph
O
CN
CN
CN
CN
1
Ph
Me2N
Nu
Ph
Nu
2B
NMe2
H
2
O
CN
O
CN
NH2
NH2
Ph
H2O2
Ph
Nu = NH2NH2
N
N
H
N
AcOH
N
H
5
4
O
CN
2B
Ph
Me2N
NMe
-
2
O
NH2
N
CN
Ph
H
6
NH2
N
Nu = NH3
O
CN
CN
H
3
Ph
NH2
7
The dihydropyridazine 9 was readily oxidized to 11 on attempted coupling with benzenediazonium
chloride. Compound 11 was also obtained upon oxidizing 9 in an AcOH-H2O2 mixture (Scheme 2).
Reduction of 1 with sodium borohydride in propanol solution afforded 2-amino-5-phenyl-4,5-
dihydrofuran-3-carbonitrile (12) in 60% yield (Scheme 2). This compound has been synthesized earlier
1
13
[15] in almost the same way, but no spectral data had been reported. H-NMR and C-NMR of now
reported for the first time.

Molecules 2009, 14
Scheme 2. Synthesis of 5-phenyl-4,7-dihydro-1H-pyrazolo[3,4-c]pyridazin-3-ylamine.
801
CN
NaBH4
Ph
Ph
NH2
O
12
O
NH2
NH
CH2
H2N
1
H
N
N
H
N
8
NH2NH2
N
N
NH2NH2
H
N
Ph
NH2
10
O
N
H
N
Ph
CN
9
O
N
PhN NCl
Ph
CN
11
We next shifted our interest to an exploration of the chemistry of 2-cyano-5-phenyl-3,5-
dioxopentanonitrile, reported by Abdelrazek and Salah El-Din [16] to be formed upon refluxing ethyl
benzoyl acetate and malononitrile in ethanolic piperidine solution. Unfortunately, in our hands ethyl
benzoylacetate did not react with malononitrile under the reported reaction conditions or even more
vigorous ones. Thus it is concluded that 2-cyano-5-phenyl-3,5-dioxopentanonitrile could not have
been obtained as reported. It is of interest that in the paper 2-cyano-5-phenyl-3,5-dioxopentanonitrile
was claimed to be oil and the authors have not reported analytical data.
Conclusions
In summary, we have successfully developed a simple route to pyrroles and pyridazines. Moreover,
we could show that product claimed earlier to be 4-phenacyl pyrazole-3,5-diamine (8) is really 5-
phenyl-4,7-dihydro-1H-pyrazolo[3,4-c]pyridazin-3-ylamine (10).
Experimental
General
All melting points are uncorrected and were determined on a Sanyo (Gallaenkamp) instrument.
Infrared spectra were recorded in KBr on a Perkin-Elmer 2000 FT–IR system.1H-NMR and 13C-NMR
1
spectra were determined on a Bruker DPX spectrometer operating at 400 MHz for H-NMR and 100
MHz for 13C-NMR using in CDCl3 or DMSO as solvents and TMS as internal standard; chemical

Molecules 2009, 14
802
shifts are reported in δ (ppm). Mass spectra were measured on VG Autospec Q MS 30 and MS 9 (AEI)
spectrometers, with EI 70 EV. Elemental analyses were measured by means of LEOCHNS-932
Elemental Analyzer. General purpose silica gel on polyester 20 x 20 cm TLC plates with UV indicator
were used in TLC experiments.
Synthesis of 2-(2-oxo-2-phenylethyl)malononitrile (1)
A solution of malononitrile (0.66 g, 0.01 mol) and 2-bromo-1-phenylethanone (phenacyl bromide)
(1.99 g, 0.01 mol) in ethanol (15 mL) was cooled to 0 oC. Potassium hydroxide (0.84 g, 0.15 mol) was
added and the reaction mixture was stirred (followed until completion by TLC using 1:1 ethyl acetate-
petroleum ether as eluent). The reaction was carefully quenched with ice-H2O and 1M HCl solution,
The solid so formed was collected by filtration and recrystallized from ethanol to give a white product;
yield 85 %; mp 160-62 ºC; Anal. calcd. for C11H8N2O (184.2): C, 71.73; H, 4.38; N, 15.21. Found: C,
71.68; H, 4.35; N, 15.41; IR (KBr): υmax = 2211 (2CN), 1645 (CO); 1H-NMR (DMSO): δ, ppm = 4.11
13
(d, 2H, CH2, J = 8 Hz), 5.15 (t, 1H, CH, J = 8 Hz), 7.56-8.02 (m, 5H, Ar-H); C-NMR (DMSO): δ,
ppm = 194.83, 135.29, 134.69, 129.41 (2C), 128.69 (2C), 114.88 (2CN), 38.75, 18.52. MS: m/z (%)
184 (M+, 50), 105 (100), 77 (70).
Synthesis of 2-(3-(dimethylamino)-1-oxo-1-phenylprop-2-en-2-yl)malononitrile (2)
A mixture of compound 1 (1.84 g, 0.01 mol) and N,N-dimethylformamide dimethyl acetal
(DMFDMA, 1.19 g, 0.01 mol) in toluene (10 mL) was refluxed for 4 h. The reaction mixture was
evaporated under reduced pressure yielding a crude product, which was recrystallized from toluene to
give a light yellow product; yield 75 %; mp 129-30 ºC; Anal. calcd. for C14H13N3O (239.2): C, 70.28;
H, 5.48; N, 17.56. Found: C, 70.39; H, 5.50; N, 17.44; IR (KBr): υmax = 2208 (2CN), 1633 (CO); 1H-
NMR (DMSO): δ, ppm = 3.05 (s, 3H, CH3), 3.14 (s, 3H, CH3), 7.10 (s, 1H, CH), 7.25-7.42 (m, 5H,
13
Ar-H), 8.44 (s, 1H, CH); C-NMR (DMSO): δ, ppm = 194.47, 155.33, 134.89, 134.33, 129.43 (2C),
129.04 (2C), 106.93 (2CN), 78.17, 38.31, 37.44, 18.09; MS: m/z (%) 239 (M+, 100), 210 (15), 197
(45), 140 (25), 134 (90), 119 (20), 107 (15), 77 (15), 57 (25).
Synthesis of 2-amino-4-benzoyl-1H-pyrrole-3-carbonitrile (3)
A mixture of compound 2 (2.39 g, 0.01 mol) and ammonium acetate (1 g) in acetic acid (10 mL)
was refluxed for 1 h. The mixture cooled and then was poured onto ice-water. The solid thus formed
was collected by filtration and recrystallized from petroleum ether to give colorless crystals; yield 60
%; mp 297-98 ºC. Anal. calcd. for C12H9N3O (211.2): C, 68.24; H, 4.29; N, 19.89. Found: C, 68.23; H,
1
4.31; N, 19.79; IR (KBr): υmax = 3350, 3330 (NH2), 3134 (NH), 2220 (CN), 1656 (CO); H-NMR
(DMSO): δ, ppm = 7.33-7.80 (m, 8H, Ar-H, NH2, D2O exchangeable, NH, D2O exchangeable), 8.18
13
(s, 1H, CH); C-NMR (DMSO): δ, ppm = 189.57, 166.25, 158.65, 154.01, 150.03, 129.23 (2C),
128.76, 124.15 (2C), 102.14, 99.13; MS: m/z (%) 211 (M+, 100), 184 (80), 155 (80), 141 (25), 114
(10), 105 (25), 77 (45).

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Synthesis of 3-amino-5-benzoyl-1,2-dihydropyridazine-4-carbonitrile (4)
A mixture of compound 2 (2.39 g, 0.01 mol) and hydrazine hydrate (0.5 g, 0.01 mol) in ethanol (10
mL) was refluxed for 5 h (monitored to completion by TIC using 1:1 ethyl acetate-petroleum ether as
eluent). The mixture cooled and then was poured onto ice-water. The solid formed was collected by
filtration and recrystallized from ethanol to give a yellow product; yield 65 %; mp 227-29 ºC; Anal.
calcd. for C12H10N4O (226.2): C, 63.71; H, 4.46; N, 24.76. Found: C, 63.55; H, 4.36; N, 24.89; IR
(KBr): υmax = 3409, 3330 (NH2), 3080 (NH), 3060 (NH), 2200 (CN), 1608 (CO); 1H-NMR (DMSO):
δ, ppm = 4.76 (br, 2H, NH2, D2O exchangeable), 7.39-7.82 (m, 8H, Ar-H), 8.20 (br, 1H, NH, D2O
13
exchangeable), 9.09 (br, 1H, NH, D2O exchangeable); C-NMR (DMSO): δ, ppm = 192, 166.59,
160.54, 158.34, 149.83, 129.30 (2C), 129.18, 124.34 (2C), 109.24, 99.67; MS: m/z (%) 226 (M+, 100),
209 (10), 196 (25), 182 (20), 168 (10), 154 (25), 114 (10), 105 (20), 77 (20).
Synthesis of compound 3-amino-5-benzoylpyridazine-4-carbonitrile (5)
A mixture of 4 (2.26 g, 0.01 mol) and hydrogen peroxide 100% (3 mL) in acetic acid (10 mL) was
refluxed for 2 h (followed to completion by TLC using 1:1 ethyl acetate-petroleum ether as eluent).
The mixture was cooled and then poured onto ice-water. The solid formed was collected by filtration
and recrystallized from ethanol to give a dark yellow product; yield 55 %; mp 148-150 ºC; Anal. calcd.
for C12H18N4O (226.2): C, 64.28; H,3.60; N, 24.99. Found: C, 64.02; H, 3.81; N, 24.75; IR (KBr): υmax
1
= 3380, 3212 (NH2), 2281 (CN), 1643 (CO); H-NMR (DMSO): δ, ppm = 5.56 (br, 2H, NH2, D2O
13
exchangeable), 7.57 -8.12 (m, 5H, Ar-H), 8.35 (s, 1H, CH); C-NMR (DMSO): δ, ppm = 191.32,
176.53, 154.54, 143.39, 129.99 (2C), 126.34 (2C), 121.54, 118.46, 111.42, 100.98; MS: m/z (%) 224
(M+, 75), 206 (15), 196 (50), 180 (25), 164 (10), 154 (35), 128 (10), 105 (45), 77 (50).
Syntheses of 3-oxo-6-phenyl-2,3,4,5-tetrahydropyridazine-4-carbonitrile (9) and 5-phenyl-4,7-
dihydro-1H-pyrazolo[3,4-c]pyridazin-3-ylamine (10).
Procedure 1: A mixture of compound 1 (1.84 g, 0.01 mol) and hydrazine hydrate (0.50 g, 0.01 mol)
in ethanol (10 mL) was stirred for 8 h at room temperature (followed by TLC until completion using
ethyl acetate-petroleum ether 1:1 as eluent). The reaction mixture was poured onto ice-water. The solid
product formed was collected by filtration and crystallized from ethanol to give white product 9 in
90% yield.
Procedure 2: A mixture of compound 1 (1.84 g, 0.01 mol) and hydrazine hydrate (0.50 g, 0.01 mol)
in ethanol (10 mL) was refluxed for 5 h (followed by TLC until completion using ethyl acetate-
petroleum ether 1:1 as eluent). The reaction mixture was cooled and poured onto ice-water. The solid
product thus formed was collected by filtration and washed with hot ethanol to extract the white
product 9. The residue was crystallized from N,N-dimethylformamide (DMF) to yield purple crystals
of 10.

Molecules 2009, 14
804
Compound 9: Yield 35 %; mp 253-55 ºC. Anal. calcd. for C11H9N3O (199.2): C, 66.32; H, 4.55; N,
1
21.09. Found: C, 66.54; H, 4.32; N, 21.30. IR (KBr): υmax = 3234 (NH), 2154 (CN), 1693 (CO); H-
NMR (DMSO): δ, ppm = 3.27 (dd, 1H, J = 12.6, 6.0), 3.59 (dd, 1H, J = 12.6, 6.0), 4.50 (dd, 1H, J =
13
13.2, 6.0), 7.45-7.79 (m, 5H, Ar-H), 11.49 (br, 1H, NH, D2O exchangeable); C-NMR (DMSO): δ,
ppm = 159.81, 148.66, 134.91, 129.91, 126.99 (2C), 125.75 (2C), 116.92 (CN), 29.90, 25.61; MS: m/z
(%) 199 (M+, 100), 170 (15), 155 (15), 140 (15), 115 (25), 103 (80), 77 (35).
Compound 10: Yield 65 %; mp 288-90 ºC. Anal. calcd. for C11H11N5 (213.2): C, 61.96; H, 5.20; N,
32.84. Found: C, 61.77; H, 5.32; N, 32.65. IR (KBr): υmax = 3159, 3012 (NH2), 3012 (NH), 2983
1
(NH); H-NMR (DMSO): δ, ppm = 3.57 (s, 2H, 4-H), 7.33 (m, 1H, p-H, phenyl), 7.39 (m, 2H, m-H,
phenyl), 7.70 (m, o-H, phenyl), 10.11 (br. s, 1H, 7-H, D2O exchangeable), the other NH signals are too
13
broad to be localized; C-NMR (DMSO): δ, ppm = 154.1, 146.7 (C-5), 138.0 (br., C-3a and C-7a),
137.8 (i-C), 128.3 (m-C), 128.1 (p-C), 124.7 (o-C), 77.7 (C-3a), 21.3 (C-4); MS: m/z (%) 214 (M+,
100), 185 (35), 171 (15), 141 (15), 115 (25), 77 (35).
Synthesis of 3-Oxo-6-phenyl-2,3-dihydropyridazine-4-carbonitrile (11)
A cold solution of phenyldiazonium chloride (0.01 mol) was prepared by adding a solution of
sodium nitrite (0.7 g into 10 mL H2O) to a cold solution of aniline hydrochloride (0.93 g, 0.01 mol of
aniline in 5 mL concentrated HC1) with stirring at room temperature. The resulting solution of
phenyldiazonium chloride was then added to a cold solution of compound 9 (1.99 g, 0.01 mol) in
ethanol (50 mL) containing sodium acetate (2 g). The reaction mixture was stirred for 1 hr. The solid
product formed was collected by filtration and crystallized from ethanol to give a yellow product, yield
70 %; mp 295-97 ºC. Anal. calcd. for C11H7N3O (197.2): C, 67.00; H, 3.58; N, 21.31. Found: C, 66.98;
H, 3.92; N, 21.65. IR (KBr): υmax = 3217 (NH), 2233 (CN), 1664 (CO); 1H-NMR (DMSO): δ, ppm =
7.46-7.91 (m, 5H, Ar-H), 8.85 (s, 1H, CH), 14.04 (br, 1H, NH, D2O exchangeable); 13C-NMR
(DMSO): δ, ppm = 158.78, 148.35, 142.99, 138.34, 135.90, 130.34 (2C), 128.22 (2C), 119.26, 114.66.
MS: m/z (%) 197 (M+, 100), 169 (65), 140 (95), 114 (35), 102 (40), 77 (35), 63 (20).
Synthesis of 2-amino-5-phenyl-4,5-dihydrofuran-3-carbonitrile (12)
o
A solution of compound 1 (1.84 g, 0.01 mol) in isopropanol (5 mL) was cooled to 0 C. Sodium
borohydride (0.756 g, 0.02 mol) was added and the reaction mixture was stirred for several hours
(followed by TLC using ethyl acetate-petroleum ether 1:1 as eluent). If any starting compound was
present, more sodium borohydride (up to 0.6 equivalents) was added. The reaction was carefully
quenched with ice-H2O and 1M HCl solution, extracted with dichloromethane, filtered, and
concentrated. The crude product was recrystallized from petroleum ether bp 60-80°C to give colorless
crystals; yield 60 %; mp 116-18 ºC. Anal. calcd. for C11H10N2O (186.21): C, 70.95; H, 5.41; N, 15.04.
1
Found: C, 71.05; H, 5.36; N, 14.84. IR (KBr): υmax = 3321, 3267 (NH2), 2187 (CN); H-NMR
(CDCl3): δ, ppm = 2.93 (dd, 1H, J = 12.4, 8), 3.313 (dd, 1H, J = 12.0, 8.0), 4.84 (br, 2H, NH2, D2O
13
exchangeable), 5.64 (dd, 1H, J = 12.4, 8.0), 7.28-7.44 (m, 5H, Ar-H); C-NMR (DMSO): δ, ppm =

Molecules 2009, 14
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167.67, 140.60, 128.57 (2C), 128.23, 125.66 (2C), 119.98, 82.28, 46.39, 36.60. MS: m/z (%) 186 (M+,
100), 169 (45), 143 (80), 115 (95), 106 (15), 77 (45), 63 (15).
Acknowledgements
The authors are grateful to Kuwait University Research Administration for the financial support of
project SC10/06 and for SAF facilities project GS01/02 and GS03/01.
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Sample Availability: Samples of compounds 1-12 are available from the authors.
© 2009 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
This article is an open-access article distributed under the terms and conditions of the Creative
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