A simple and efficient synthesis of 3-amino-5-benzyl-6-phenylpyridazine-4- carbonitrile

Article abstract of DOI:10.1016/j.tetlet.2013.03.077

3-Amino-5-benzyl-6-pyridazine-4-carbonitrile has been synthesized by the reaction of 4-substituted thiosemicarbazides with (2,3-diphenylcyclopropen-1- ylidene)propanedinitrile. The structure of the pyridazine derivative has been confirmed unambiguously by single crystal X-ray crystallography.

Full text of DOI:10.1016/j.tetlet.2013.03.077

Accepted Manuscript
A simple and efficient synthesis of 3-amino-5-benzyl-6-phenylpyridazine-4-
carbonitrile
Alaa A. Hassan, Sara M. Mostafa, Stefan Bräse, Martin Nieger
PII:
S0040-4039(13)00479-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.03.077
TETL 42702
Reference:
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
25 November 2012
3 March 2013
13 March 2013
Please cite this article as: Hassan, A.A., Mostafa, S.M., Bräse, S., Nieger, M., A simple and efficient synthesis of
3-amino-5-benzyl-6-phenylpyridazine-4-carbonitrile, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/
j.tetlet.2013.03.077
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1
Tetrahedron Letters
journal hom epage: www.elsevier.com
A simple and efficient synthesis of 3-amino-5-benzyl-6-phenylpyridazine-4-
carbonitrile
Alaa A. Hassan a,∗, Sara M. Mostafa a, Stefan Bräse b, Martin Nieger c
aChemistry Department, Faculty of Science, Minia University, 61519 El-Minia, Egypt
bInstitute of Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
c Laboratory of Inorganic Chemistry, Department of Chemistry, University of Helsinki, P.O. Box 55, 00014 Helsinki, Finland
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
3-Amino-5-benzyl-6-pyridazine-4-carbonitrile has been synthesized by the reaction of 4-
substituted thiosemicarbazides with (2,3-diphenylcyclopropen-1-ylidene)propanedinitrile. The
structure of the pyridazine derivative has been confirmed unambiguously by single crystal X-ray
crystallography.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
4-Substituted thiosemicarbazides
(2,3-Diphenylcyclopropen-1-ylidene)propanedinitrile
Pyridazine derivatives
Condensation reaction
X-ray crystallography
Pyridazines are important building blocks in a variety of
pharmaceutical agents and biologically active products.1-3 Several
substituted pyridazines have been found to exhibit a wide range
of biological activities, which include antiviral,4 anticancer,4,5
antituberculosis,6 antihypertensive,7-9 antifungal,10,11 and
antimicrobial.12,13 Pyridazine derivatives have also been the
subject of extensive research in the agrochemical field.14,15
Moreover, pyridazines are useful intermediates for the
construction of several other heterocycles.16,17
tetrahydroazocines,
azabicyclo[4.3.0]non-2-enes
and
cycloheptadienes, respectively. A series of [1-aryl-2-arylamino-
5,6-diphenyl-4(1H)-pyridinylidene]propanedinitriles has been
synthesized by the reaction of N1,N2-diarylamidines with 2 via a
formal [3+3] cycloaddition reaction, followed by thermal
dehydrogenation.28
In this paper we describe the synthesis of the novel compound,
3-amino-5-benzyl-6-phenylpyridazine-4-carbonitrile (3) from the
reaction of 4-substituted thiosemicarbazides 1a-c and triafulvene
(2), by refluxing equimolar amounts of the reactants in ethyl
acetate/piperidine as the solvent. Product 3 was obtained as a
crystalline solid in 67−81% yield (Scheme 1).31
Thiosemicarbazides, with their multifunctional groups, would
appear to be ideal candidates for the development of new
methodologies for the synthesis of pyrazoles,18 1,2,3-triazoles,19
1,3,4-thiadiazoles,20,21 1,3-thiazoles,22 1,3,4-thiadiazines,23 1,3,4-
thiadiazepines18 and pyridazines. 24
Compound 3 shows IR absorptions for the NH2 group at 3380
cm-1 and one band corresponding to the C≡N group at 2225 cm-1,
as well as strong bands at 1645 and 1630 cm-1 due to the C=N
bonds. The 1H-NMR spectrum of 3 showed signals for the
benzylic-CH2 at δH 4.18, the NH2 protons at δH 5.90 and the
aromatic protons at δH 6.84-7.44. In the 13C NMR spectrum of 3,
the signal at δC 37.09 was assigned to the benzylic-CH2. By
consulting the DEPT 135/90 spectra, the quaternary carbon
signal at δC 113.82 was attributed to the nitrile carbon atom. The
signals at δC 142.42 and δC 154.89 were assigned to the
Small ring systems containing double bonds in restricted
orientations have long been of considerable interest,21,25-27 in
particular, (2,3-diphenylcyclopropen-1-ylidene)propanedinitrile
(triafulvene, 2).28, 29
Eicher and co-workers reported the cycloaddition reactions
between 2 and dihydroisoquinolines,29 enamine tautomers of
pyrrolines,29 2,3,4,4a,5,6,7,8-octahydroquinoline29 and 1-
morpholinobuta-1,3-diene30 to give pyridinoisoquinolines,
———
∗ Corresponding author. Tel.: +2-086-236-3011 ; fax: +2-086-236-3011; e-mail: alaahassan2001@yahoo.com

2
Tetrahedron Letters
Ph
Step 1
pyridazine ring atoms C-5 and C-6, respectively. The pyridazine
C-3 and C-4 carbons resonated at δC 157.39 and δC 98.99,
respectively, in accordance with the observed trends in δ values
for C-atoms in push-pull systems.32, 33
S
Ph
Ph
CN
C
CN
CN
R
NH2
N
H
N
H
NH
Ph
NH
HN
N
1a-c
2
HS
4
R
Step 2
CN
H+
H+
H
CN
CN
Ph
Ph
Ph
Ph
Step 3
Step 4
NH2
NH2
NH
Ph
Ph
N
HN
N
N
- R-N=C=S
NH
R
N
N
H
H
HS
6
Scheme 1. Reaction between (2,3-diphenylcyclopropen-1-
ylidene)propanedinitrile (2) and 4-substituted thiosemicarbazides
Ph
Ph
CN
NH2
5
1.
N
N
3
From the elemental analysis and mass spectrometry, the found
molecular formula (C18H14N4) represents a product derived from
one molecule each of 1 and 2 with the loss of one molecule of R-
N=C=S.
Scheme 2. Mechanistic rationale for the formation of 3.
In conclusion, an unusual ring-opening of a cyclopropenone
with formal inclusion of hydrazine gave rise to a pyridazine
which was unequivocally characterized by X-ray crystallography.
The present investigation revealed that the product was obtained
from the nucleophilic addition of substituted thiosemicarbazides
1a-c to (2,3-diphenylcyclopropen-1-ylidene)-propanedinitrile
(triafulvene, 2), followed by heterocyclization via attack of the
NH2 group on the double bond of 2 to form novel 3-amino-5-
benzyl-6-phenylpyridazine-4-carbo-nitrile (3).
The X-ray structure of 3 (Figure 1 and Tables S1-7, in the
supplementary data) revealed the presence of 3-amino-5-benzyl-
6-phenylpyridazine-4-carbonitrile (3) along with
a
non
merohedral twin. The bond length C41-N41= 1.143 Å (note that
the crystallographic numbering does not adhere to the systematic
IUPAC numbering) corresponds to a C=N double bond.
Compound 3 is considerably congested. This is documented by
the deviation of the C4-C41-N41 bond angle by 2.6°, from
planarity (Table S3). The dihedral angles, C5-C51-C52-C53 and
C5-C6-C61-C62 with the values −37.5° and −45.8°, respectively,
clearly indicate that compound 3 is sterically crowded. Due to
this steric congestion, there is substantial twisting of the phenyl
and benzyl groups out of the plane of the pyridazine moiety.
Also, carbon atoms C3-C6, C52-C57 and C61-C66 are arranged
in planar fashion, since the bond angles about these centers
summate to 360°. On the other hand, the sum of the angles C5-
C51-C52, C5-C51-H(51A) and C52-C51-H(51A) is 331-3°,
revealing pyramidalization at C51.
Single crystal X-ray structure determination of 3
Suitable crystals were obtained by recrystallization from
acetonitrile. The single crystal X-ray diffraction study was
carried out on a Bruker Apex Duo diffractometer at 120 (2) K
using MoKα (λ= 0.71073 Å) radiation. Direct methods
(SHELXS-97)34 were used for structure solution and refinement
was carried out using SHELXL-9734 (full-matrix least-squares on
F2). Hydrogen atoms were localized by difference electron
density determination and refined using a riding model [H(N)
free]. The crystal is a non-merohedral twin with 2 domains
[BASF = 0.214(4)].
C18H14N4 Mr= 286.33 g mol-1, colorless crystals, crystal size
0.16 × 0.08 × 0.04 nm, triclinic, space group P-1(2), a =5.6677(5)
Å, b= 9.7831(8) Å, c= 13.5872(12) Å, α = 94.120(4)°, β =
97.359(5)°, γ = 102.205(4)°, V= 726.47(11) A3, Z= 2, Dcalcd=
1.309 Mg m-3, F(000) = 300, µ= 0.081 mm-1, T= 120 (2) K, 3161
reflections (2θmax = 55°), 3161 unique [Rint= 0.0000], 206
parameters, 2 restraints, R1 (for 2086 I > 2σ(I)) = 0.066, wR2 (all
data) = 0.188, S = 1.16, largest diff. peak and hole= 0.340/-
0.294eA-3.
Crystallographic data (excluding structure factors) for the
structure reported in this work have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 910226 (compound 3). Copies of the data
can be obtained free of charge on application to The Director,
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax:
+44(1223)336-033; e-mail: deposit@ccdc.cam.ac.uk).
References and notes
Figure 1: Molecular structure of 3 (ORTEP, displacement parameters are
drawn at the 50% probability level). The crystallographic numbering does not
reflect the systematic IUPAC numbering.
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A rationale for the formation of product 3 is presented in
Scheme 2. The NH2 group first attacks the double bond of 2,
eventually forming the substituted pyridazine 3 via steps 1-4.

3
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31. General Procedure: The thiosemicarbazide 1a-c (1.0 mmol) was
dissolved in 15 ml of EtOAc with two drops of piperidine and
added to (2,3-diphenylcyclopropen-1-ylidene)propanedinitrile (2)
(1 mmol) in 25 ml of EtOAc. The mixture was heated under reflux
for 3 h (the reaction was monitored by TLC). The solvent was
concentrated and the residue was subjected to preparative thin
layer chromatography using toluene/ EtOAc (2:1) as the
developing solvent to give one main zone. This zone was
extracted and recrystallized from MeCN. 3- Amino-5-benzyl-6-
phenylpyridazine-4-carbonitrile (3). Colourless crystals (0.217 g,
76%), m.p 170- 172 °C MeCN. IR (KBr) υ = 3380 (NH2), 2225
1
(CN), 1645, 1630 (C=N), 1585 (Ar-C=C). H-NMR (CDCl3): δH =
7.44-7.38 (m, 5H, Ar-H), 7.36-7.19 (m, 3H, Ar-H), 6.88-6.84 (m,
2H, Ar-H), 5.90 (br s, 2H, NH2), 4.18 (s, 2H, CH2-Ph). 13C-NMR
(CDCl3): δC= 157.39 (pyridazine-C-3), 154.89 (pyridazine-
C-6), 142.42 (pyridazine-C-5), 136.22 and 135.91 (Ar-
CH), 129.19, 128.93, 128.73, 128.40 and 127.13 (Ar-CH),
113.82 (C≡N), 98.99 (pyridazine-C-4), 37.09 (CH2-Ph). MS (EI):
m/z= 286 (M+, 100), 270 (12), 259 (11), 152 (17), 91 (42), 77 (27),
66 (21). Anal. Calcd for C18H14N4 (286.12): C, 75.50; H, 4.93; N,
19.57. Found: C, 75.37; H, 5.08; N, 19.46.
32. Kalinowski, H.-O, Berger, S.; Braun, S. (13C-NMR Spectroscopy),
Thieme, Stuttgart, 1984, pp 121
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