Phenacylmalononitrile 3 reacts with hydrazine hydrate in refluxing dioxan to afford the iminopyridazine derivative 6 and the pyrazolo[3,4-c]pyridazine derivative 7.Compound 3 reacts also with phenylhydrazine in refluxing ethanol to afford the iminopyridazine derivative 11 along with the phenylhydrazone derivative 12. Compound 12 could be cyclized into the pyrazolo[3,4-c]pyridazine derivative 13 upon reflux with sodium ethoxide

Abdelrazek, Fathy M.

Mohamed, Ashraf M.

Revistes Catalanes amb Accés Obert

56 AFINIDAD LXV, 533, Enero-Febrero 2008
Reinvestigation of the Reaction
of PhenacylMalononitrile with
Hydrazines under Solvent Conditions
Fathy M. Abdelrazek1*, Ashraf M. Mohamed2
1Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
2Department of Applied Organic Chemistry, National Research Center, Dokki, Giza, Egypt 
Nueva investigación de la reacción de fenacilmalononitrilo con hidrazinas en disolución
Nova investigació de la reacció de fenacilmalononitril amb hidrazines en dissolució
Recibido: 21 de mayo de 2007; aceptado: 21 de septiembre de 2007
RESUMEN
El fenacilmalononitrilo 3 reacciona con hidrato de hidra-
zina en dioxano a reflujo para dar el derivado de imino-
piridazina 6 y el derivado de pirazolo[3,4-c]piridazina 7.
El compuesto 3 reacciona también con fenilhidrazina en
etanol a reflujo rindiendo el derivado de iminopiridazina
11 junto con el derivado de fenilhidrazona 12. El com-
puesto 12 cicla para dar el derivado de pirazolo[3,4-c]piri-
dazina 13 por reflujo con etóxido sódico.
Palabras clave: Fenacilmalononitrilo. 3,5-diamino-4-fena-
cilpirazolas. Aminopiridazinas. Pirazolo[3,4-c]piridazinas.
SUMMARY
Phenacylmalononitrile 3 reacts with hydrazine hydrate
in refluxing dioxan to afford the iminopyridazine deriva-
tive 6 and the pyrazolo[3,4-c]pyridazine derivative 7.
Compound 3 reacts also with phenylhydrazine in reflu-
xing ethanol to afford the iminopyridazine derivative 11
along with the phenylhydrazone derivative 12. Compound
12 could be cyclized into the pyrazolo[3,4-c]pyridazine
derivative 13 upon reflux with sodium ethoxide.
Key words: Phenacylmalononitrile. 3,5-Diamino-4-phe-
nacylpyrazoles. Aminopyridazines and pyrazolo[3,4-c]pyri-
dazines.
RESUM 
El fenacilmalononitril 3 reacciona amb hidrat d’hidrazi-
na en dioxà a reflux donant el derivat d’iminopiridazina
6 i el derivat de pirazolo[3,4-c]piridazina 7. El compost 3
reacciona també amb fenilhidrazina en etanol a reflux
rendint el derivat d’iminopiridazina 11 junt amb el deri-
vat de fenilhidrazona 12. El compost 12 ciclitza per donar
el derivat de pirazolo[3,4-c]piridazina 13 per reflux amb
etòxid sòdic.
Mots clau: Fenacilmalononitril. 3,5-diamino-4-fenacilpi-
razoles. Aminopiridazines. Pirazolo[3,4-c]piridazines.
* All Correspondance should be addressed to:
Prof. Dr. Fathy Mohamed Abdelrazek
Phone: Home 00202 3301651
E-mail: prof_fmrazek@yahoo.com
TRIPA 533  13/5/08  10:59  Página 56
INTRODUCTION
In the past few years we have been involved in a program
aimed at the synthesis of some new heterocyclic systems
of biological interest to be tested as biodegradable agro-
chemicals(1-4). In the context of this program we have pre-
viously reported a novel synthesis of phenacyl malononi-
trile 3 (Scheme 1) and its transformation into
3,5-diaminopyrazole derivatives 4a,b(5). This work was furt-
her elaborated and we could get a variety of com-
pounds[6-8]. During a routine literature search, we have been
faced by a paper published by Elnagdi et. al.[9] claiming that
they invented the reaction of phenacyl bromide with malo-
nonitrile in presence of sodium hydroxide to give higher
yield of phenacyl malononitrile 3 ignoring that this reaction
is well known in the literature(10). They claimed also that the
reaction of 3 with hydrazine hydrate afforded compounds
4a and 5 (Scheme 1) (2 & 5 in the original paper[9] ); and with
phenyl hydrazine to afford the phenylhydrazide 9 which
was cyclized into 10 (Scheme 1) (7 and 8 in the original
paper(9)). The melting point cited in this paper for compound
4a (their 2) is 290-291 °C; while its reported mp. is 218-
220 °C(5). Structure 5 (their 5) is not likely to be obtained
from this reaction, but rather logic compound 6 (the inter-
mediate 4 in their paper) should have been the final pro-
duct since the hydrolysis of the imino group into a carbonyl
group is not likely to occur so simply with water under the
reaction conditions. The formation of the phenylhydrazide
9 (their 7) seemed doubtful and even if this imaginary com-
pound was true; its cyclization would not lead to the pyra-
zolone 10 (Scheme 1) (their 8(9); wrongly drawn); unless
some mysterious rearrangement leading to transfer of the
phenyl group from the terminal N to the next N is opera-
ting. The numbers of compounds 15 and 17 in their third
scheme; should be 16 and 18(9), Furthermore, in their struc-
tures 18a,b (the ring C=O should be C-NH2; and the mole-
cular formulae are calculated on the wrong structures and
the found analysis values are fabricated to fit with the cal-
culated)(9). Finally, in the experimental part the preparations
and data for compounds 19 and 21 (in their paper [9]) are
repeated twice, and the data are different in these repea-
ted parts.  
All these discrepancies raised the doubt in the factual accu-
racy of this work. Therefore it was decided to reinvestiga-
te the most significant reactions, and the data encounte-
red seemed worth to publish.  
RESULTS AND DISCUSSION
In our hands the reaction of 3 with hydrazine hydrate was
repeated in refluxing dioxan (the same reaction conditions
of Elnagdi et. al.(9)), and we could isolate two products with
melting points 233 °C and 292 °C  (233 & 290 as descri-
bed by Elnagdi et. al.(9)). Based on the analytical and spec-
tral data the lower mp. product (233 °C) was found to be
the tetrahydropyridazine imine structure 6 (Scheme 1) (the
intermediate 4 in the original paper(9) ). The 1H and 13C NMR
data given for structure 5 in ref.(9) better fits to the imi-
nopyridazine structure 6 (Scheme 1) since the 13C signal
at δ = 159.79 ppm is most probably due to the C=NH rat-
her than the C=O which should appear at much lower field
(below 175 ppm), and also the stretching frequency in the
IR spectrum given at υ = 1630 cm–1 is very low to a lactam
carbonyl group and better fits to C=NH(11); and even they
stated in their paper that the IR spectrum showed two
band at υ3250 and 3200 cm–1 and assigned them to two
NH which is applicable to our structure 6 rather than their
structure 5. The analyses seem to be put as required by
their wrong structure 5.
The higher mp. product (292 °C) showed a molecular ion
peak in the mass spectrum at m/z 213. The IR spectrum of
this product showed no carbonyl absorptions and the pre-
sence of only amino absorption bands at υ3320-3150 cm–1.
The 1H NMR spectrum of this product revealed a singlet
(2H) at δ 3.7 ppm, an aromatic multiplet (8H) at δ 7.3-7.9
ppm and a singlet (1H) at δ 10.35 ppm. On the basis of the-
se data the pyrazolo[3,4-c]pyridazine structure 7 was assig-
ned.
It seems that in refluxing dioxan two competitive reactions
are working: 1st is the condensation of hydrazine hydrate
with the carbonyl group of 3 followed by addition of the
hydrazone NH2 to one of the cyano groups to afford 6. 2
nd
is the cycloaddition of hydrazine to the two cyano groups
of 3 to afford the 4-phenacyl-3,5-diaminopyrazole 4a which
undergoes an insitu condensation with hydrazine hydrate
to afford the hydrazone intermediate 8 (Scheme 1), which
in its role undergoes cyclization with elimination of ammo-
nia via the nucleophilic attack of the hydrazone NH2 on the
ring amino group to give 7. Compound 7 has also been
previously reported to be obtained from the reaction of 4a
with hydrazine hydrate (lit. mp. 293 °C)(8). 
Thus it evident that the pyrazole derivative 4a (scheme 1)
(no. 2 in ref.(9)) is not isolated from this reaction under the-
se reaction conditions. The wrong assignment given by
Elnagdi et. al.(9) has serious consequences for some other
reactions involved in their paper and based on the their
claimed 2; for example structures 13-21 are all doubtful.    
The reaction of 3 with phenyl hydrazine in refluxing etha-
nol was also claimed to afford the phenylhydrazide 9 as
the only product, which was cyclized to the pyrazolone 10
(scheme 1); (7, 8 in the original paper(9); 8 is wrongly drawn).
In our hands this reaction also afforded two products: The
first product with mp. 177 °C showed analyses and spec-
tra that suggested the tetrahydropyridazine imine structu-
re 11 to be assigned to it (Scheme 1; cf. experimental; not
isolated by Elnagdi et. al.(9)). 
The second product is a yellow crystalline product of mp.
200 °C (this perhaps what happened with Elnagdi et. al.;
mp.199-200 °C(9) ): This product showed a molecular ion
peak in the mass spectrum at m/z 382. The IR spectrum of
this product did not show any carbonyl absorption bands.
The 1H NMR spectrum revealed only a singlet (2H) at δ 2.85
ppm, a multiplet (17H) at δ 6.55-7.85 ppm assignable to
three phenyl rings and NH2 protons and two singlets at 8.15
and 10.45 ppm (2H & 1H; D2O exchangeable due to NH2 &
hydrazone NH respectively). Based on these spectral as
well as analytical data the phenyl hydrazone structure 12
was assigned to this product. 
It is assumed that phenacylmalononitrile 3 reacts with
phenyl hydrazine in refluxing 96% ethanol (the same reac-
tion conditions described by Elnagdi et. al.(9) ) following the
same route as its reaction with hydrazine hydrate to afford
11 and the 3,5-diaminopyrazole derivative 4b, which under-
goes an insitu condensation with phenyl hydrazine to give
the corresponding phenyl hydrazone 12. 
To confirm this hypothesis the 3,5-diaminopyrazole deri-
vative 4b was prepared separately as described before(5)
and allowed to react with phenyl hydrazine in refluxing
ethanol for 2h, the obtained product was found to match
completely with compound 12.
Refluxing compound 12 in ethanol with sodium ethoxi-
de afforded a new compound of mp. 222 °C. The IR
spectrum of this product did not show any carbonyl
absorption bands. The 1H NMR spectrum revealed only
a singlet (2H) at δ 3.45 ppm and a multiplet (17H) at δ
7.35-7.85 ppm assignable to three phenyl rings and NH2
protons. Based on these spectral as well as analytical
data the pyrazolo[3,4-c]pyridazine derivative 13 was
assigned to this product (this perhaps what happened
with Elnagdi et. al. (9), but they failed to interpret the
AFINIDAD LXV, 533, Enero-Febrero 2008 57
TRIPA 533  13/5/08  10:59  Página 57
results). It should be clarified that the intermediate hydra-
zone 8 could not be isolated but undergoes insitu cycli-
zation into 7; while the phenyl hydrazone 12 could be
separated and then cyclized into 13 upon reflux with
sodium ethoxide. This perhaps may be due to the ste-
ric factors as well as the strong nucleophilicity of the
hydrazone NH2 rather than the phenyl hydrazone NHPh
which needed more drastic conditions to accomplish
its cyclization. 
The 13C NMR data of compound 13 confirmed its structu-
re. It revealed a one C(t) at δ 16.35 ppm attributable to the
pyridazine ring CH2 and no signals below δ 160 ppm that
can be attributed to carbonyl carbons (cf. experimental).
A structure like 10 (Scheme 1) (8 in ref.(9) ) should have reve-
aled the methylene carbon at ca. δ 35 ppm and two car-
bonyl carbons at ca. δ 165 and 195 ppm for the ring car-
bonyl and the side chain carbonyl respectively(11). 
It is worth to mention that the products of this last reac-
tion depend on the molar ratio of phenyl hydrazine and the
time of the reaction. Thus when the reaction was carried
out with 1:1 molar ratios of 1 and phenyl hydrazine and
refluxed for 1h; low yield of 11 and 12 was obtained along
with the pyrazole derivative 4b, but when repeated using
three fold excess of phenyl hydrazine and the reflux time
was extended to 2h, both 11 and 12 were obtained in bet-
ter yields. 
The analytical and spectral data cited in ref.(9) for com-
pounds 9 and 10 (Scheme 1) (their 7 and 8) seem to be
fabricated to coincide with these structures.         
It has also been claimed that the reaction of phenacyl bro-
mide 1 with ethyl cyanoacetate led only to the dialkylation
product(9). In our hands when phenacyl bromide 1 was allo-
wed to react with ethyl cyanoacetate in presence of sodium
hydroxide (as described by Elnagdi et. al.(9) ) only unidenti-
fiable tarry product was obtained. However the reactions
of 1 with ethyl cyanoacetate in presence of piperidine and
with the sodium salt of ethyl cyanoacetate were previously
reported by us(6).
58 AFINIDAD LXV, 533, Enero-Febrero 2008
Scheme 1
TRIPA 533  13/5/08  10:59  Página 58
CONCLUSION
The reaction of phenacylmalononitrile with hydrazine hydra-
te and phenyl hydrazine is reinvestigated under solvent
reaction conditions. Some wrong structures and claimed
results could be corrected.
Experimental Section
Melting points were determined on an electrothermal (9100)
apparatus and are uncorrected. The IR spectra were recor-
ded as KBr pellets on a Perkin Elmer 1430 spectrophoto-
meter. The 1H-and 13C NMR spectra were taken on a Varian
Gemini 300 MHz spectrometer in DMSO-d6 using TMS as
internal standard. Mass spectra were taken on a Shimadzu
GCMS-GB 1000 PX (70ev). Elemental analyses were carried
out by the Microanalytical Centre at Cairo University.
The reaction of phenacyl-malononitrile 3 with hydrazine
hydrate:
A solution of 3 (1.85 g; 0.01 mole) and hydrazine hydrate
(0.01 mole) in 100 ml of dioxan was refluxed for 2h. The
reaction mixture was allowed to cool to room temperatu-
re. The solid precipitate was filtered off, boiled in ethanol
and where a part dissolved, filtered while hot and left to
recrystallize, it was identified as 6. The insoluble part was
recrystallized from DMF/dioxan mixture (1:1) and identi-
fied as 7.
3-Imino-6-phenyl-2,3,4,5-tetrahydropyridazine-4-
carbonitrile 6:
Pale yellow crystals (0.9 g, 45%) m.p. 233-234 °C (EtOH):
IR: νmax (KBr) = 3280-3220 (NH), 2222 (CN); 
1H NMR (DMSO-
d6): δ = 3.2 (m, 2H, CH2), 4.6(dd, 1H, CH), 7.3-7.7 (m, 6H, Ph
+ ring NH) and 11.5 ppm (s, 1H, imine NH). MS [EI, 70 eV]:
m/z = [M+] (198). Analysis for C11H10N4:  calcd. C 66.65, H
5.08, N 28.26; found C 66.30, H 5.30, N 27.90.                      
5-Phenyl-4,7-dihydro-2H-pyrazolo[3,4-c]pyridazin-3-
ylamine 7:
Yellow crystalline solid, (0.85 g, 40%) mp 290-291 °C
(DMF/dioxan 1:1). IR: νmax (KBr) 3380-3190 (br., NH2 & NH);
1H NMR (DMSO-d6): δ = 2.8 (s, 2H, ring CH2), 5.15 (s, 2H,
NH2), 7.25-7.6 ppm (m, 6H, Ph+NH), 12.35 (s, 1H, pyrazo-
le NH). MS [EI, 70 eV]: m/z = [M+] (213). Analysis for C11H11N5:
calcd. C 61.96, H 5.20, N 32.84; found C 62.10, H 5.10, N
32.50.
The reaction of phenacyl-malononitrile 3 with phenyl
hydrazine:
A solution of 3 (1.85 g; 0.01 mole) and phenyl hydrazine
(0.02 mole) in 100 ml of ethanol was refluxed for 2h whe-
re a solid precipitate appeared. The reaction mixture was
filtered off while hot. The filtrate was allowed to cool to
room temperature where dark yellow product precipita-
tes, filtered off and recrystallized from ethanol to afford
dark yellow crystals which were identified as 11. The inso-
luble part was dissolved in hot ethanol with few drops of
DMF, left to cool in ice bath overnight where an orange
yellow precipitate appeared, filtered off and identified as
12.
3-Imino-2,6-diphenyl-2,3,4,5-tetrahydropyridazine-4-
carbonitrile 11:
Dark yellow crystals (1.1 g, 40%) m.p. 177-178 °C (EtOH):
IR: νmax (KBr) = 3310 & 3290 (NH), 2218 (CN); 
1H NMR (DMSO-
d6): δ = 3.25 (m, 2H, CH2), 4.45(dd, 1H, CH), 6.55-7.65 (m,
10H, 2Ph) and 11.8 ppm (s, 1H, imine NH). 13C NMR: 23.10(t),
23.43(d), 115.24(s), 115.75(d), 119.11(d), 128.60(d), 129.13(d),
129.45(d), 130.52(d), 131.35(s), 146.35(s), 156.72(s), 162.12(s).
MS: m/z = [M+] (274). Analysis for C17H14N4:  calcd. C 74.43,
H 5.14, N 20.42; found C 74.60, H 5.20, N 20.70.
1-Phenyl-4-[2-phenyl-2-(phenylhydrazono)-ethyl]-1H-
pyrazole-3,5-diamine 12:
Orange crystalline solid, (1.3 g, 34%) mp 200-201 °C
(EtOH/DMF). IR: νmax (KBr) 3385-3195 (br., NH2 & NH); 
1H
NMR (DMSO-d6): δ = 2.85 (s, 2H, CH2), 6.55-7.85 (m, 17H,
3Ph+NH2), 8.15 (s, 2H, NH2), 10.45 (s, 1H, NH). MS: m/z =
[M+] (382). Analysis for C23H22N6:  calcd. C 72.23, H 5.80, N
21.97; found C 72.10, H 5.50, N 21.60. 
Alternative preparation of 12:
A solution of 3,5-diamino-4-phenacyl-1-phenylpyrazole 4b
(1.46 g; 0.005 mole; prepared according to literature met-
hod(5) ) and phenyl hydrazine (0.54 g; 0.005 mole) in 50 ml
of ethanol was refluxed for 2h where a solid orange  pre-
cipitate appeared. The reaction mixture was then left to
cool to room temperature, filtered off and recrystallized
from ethanol/ DMF to afford orange yellow crystals iden-
tical with those of 12 in all respects. 
2,5,7-Triphenyl-4,7-dihydro-2H-pyrazolo[3,4-c]pyridazin-
3-ylamine 13:
(Cyclization of 12)
To a solution of 12 (1.91 g; 0.005 mole) in absolute etha-
nol (50 ml) was added 5 ml of sodium ethoxide (0.5 g of
Na metal dissolved in 20 ml of ethanol) and the reaction
mixture was refluxed for 2h, then left to cool to room tem-
perature and poured on ice cold water and acidified with
few drops of conc. HCl till just neutral. The solid precipi-
tate thus appeared was filtered off and washed thoroughly
with cold water, dried and recrystallized from ethanol to
afford 13 as pale yellow crystals (1.5 g; 82%); mp. 222-223
°C (EtOH). IR: νmax (KBr) 3385-3225 (br., NH2); 
1H NMR
(DMSO-d6): δ = 3.42 (s, 2H, CH2), 6.45-7.85 (m, 17H,
3Ph+NH2). 
13C NMR: 16.35(t), 92.10(s), 115.15(d), 118.75(d),
118.80(d), 126.63(d), 128.65(d), 129.12(d), 129.2(d),
129.35(d), 131.25(s), 131.55(d), 138.9(s), 145.65(s), 147.10(s),
155.65(s), 159.85(s). MS: m/z = [M+] (365). Analysis for
C23H19N5:  calcd. C 75.59, H 5.24, N 19.16; found C 75.20,
H 5.50, N 19.60.
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Reinvestigation of the Reaction of Phenacy lMalononitrile with Hydrazines under Solvent Conditions

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