Facile synthesis of 3,6-diaminopyridazine

Article abstract of DOI:10.1080/00397910701410830

An efficient two-step synthesis of 3,6-diaminopyridazine from 3,6-dichloropyridazine is reported. In this synthetic procedure, 4-methoxybenzylamine was used as a nitrogen source to substitute the chloro groups of 3,6-dichloropyridazine to form N,N'-bis-(4-methoxybenzyl)-pyridazine- 3,6-diamine. The 4-methoxybenzyl groups were then removed by treatment with hydrochloric acid to provide the target 3,6-diaminopyridazine with an overall yield of 78%. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701410830

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Facile Synthesis of 3,6‐Diaminopyridazine
Liyan Xing a b , Anne Petitjean a , Rolf Schmidt b & Louis Cuccia b
a Department of Chemistry , Queen's University , Kingston, Ontario, Canada
b Department of Chemistry and Biochemistry , Concordia University ,
Montréal, Québec, Canada
Published online: 11 Jul 2007.
To cite this article: Liyan Xing , Anne Petitjean , Rolf Schmidt & Louis Cuccia (2007) Facile Synthesis of
3,6‐Diaminopyridazine, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 37:14, 2349-2353, DOI: 10.1080/00397910701410830
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Synthetic Communicationsw, 37: 2349–2353, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701410830
Facile Synthesis of 3,6-Diaminopyridazine
Liyan Xing
Department of Chemistry, Queen’s University, Kingston, Ontario,
Canada and Department of Chemistry and Biochemistry, Concordia
´ ´
University, Montreal, Quebec, Canada
Anne Petitjean
Department of Chemistry, Queen’s University, Kingston, Ontario,
Canada
Rolf Schmidt and Louis Cuccia
Department of Chemistry and Biochemistry, Concordia University,
´ ´
Montreal, Quebec, Canada
Abstract: An efficient two-step synthesis of 3,6-diaminopyridazine from 3,6-dichloro-
pyridazine is reported. In this synthetic procedure, 4-methoxybenzylamine was used as
a nitrogen source to substitute the chloro groups of 3,6-dichloropyridazine to form
N,N0-bis-(4-methoxybenzyl)-pyridazine-3,6-diamine. The 4-methoxybenzyl groups
were then removed by treatment with hydrochloric acid to provide the target 3,6-dia-
minopyridazine with an overall yield of 78%.
Keywords: heterocycles, nucleophilic aromatic substitutions, pyridazines, supramole-
cular chemistry
INTRODUCTION
3,6-Diaminopyridazine 3 and its N-substituted derivatives are synthetic inter-
mediates of great value because they find a variety of applications in
medicinal,[1–3] coordination,[4] and supramolecular chemistry.[5] For
Received in the USA December 14, 2006
Address correspondence to Louis Cuccia, Department of Chemistry and Biochem-
´ ´
istry, Concordia University, 7141 Sherbrooke Street West, Montreal, Quebec, Canada
H4B 1R6. E-mail: cuccial@alcor.concordia.ca
2349

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L. Xing et al.
instance, diaminopyridazine-based compounds are active as g-aminobutyric
acid (GABA) brain receptor ligands,[3] cyclic guanosine monophosphate
(cGMP) phosphodiesterase inhibitors for the treatment of cardiovascular
and sexual dysfunctions,[2] and anticancer and antiparasitic agents[1]
(Scheme 1). Bearing the useful DAAD (donor–acceptor–acceptor–donor)
array of hydrogen bonding sites, they serve as important building blocks in
supramolecular chemistry.[5] A practical and facile synthetic access to 3,6-dia-
minopyridazine is therefore valuable.
To date, four syntheses of 3,6-diaminopyridazine have been reported in
the literature. However, these methods are plagued by lengthy multistep
sequences, hazardous and/or explosive intermediates, and relatively low
overall yields. In 1960, Gortinskaya and Shchukina synthesized 3,6-diamino-
pyridazine from 3-amino-6-chloropyridazine in 16% yield using aqueous
ammonia as the aminating agent.[6] However, this procedure was difficult
to reproduce by Barlin, who, in 1976, reported an alternate synthesis of 3,6-di-
aminopyridazine involving Raney nickel–catalyzed hydrogenation of
3,6-dihydrazinopyridazine.[7–9] In 1991, Deeb et al. published a synthesis of
3,6-diaminopyridazine by a Staudinger-type reduction of 6-azidotetra-
zolo[1,5-b]pyridazine followed by hydrolysis of the resulting iminophosphor-
ane.[10] Most recently, Gong and Krische reported a modification of Deeb’s
procedure wherein 6-chlorotetrazolo[1,5-b]pyridazine is condensed with
ammonia prior to Staudinger reduction.[5,11] Notably, all of the aforementioned
procedures employ 3,6-dichloropyridazine 1 as the primary starting material.
Herein we report an efficient two-step procedure to prepare 3,6-diamino-
pyridazine 3 from 3,6-dichloropyridazine 1 and 4-methoxybenzylamine
(Scheme 2).
RESULTS AND DISCUSSION
The use of 4-methoxybenzylamine as an ammonia synthon was desirable,
because 4-methoxybenzyl (PMB)–protected amines are readily hydrolyzed
upon treatment with acid. For example, Zimmerman’s group recently
Scheme 1. a) GABA receptor ligands made of disubstituted diaminopyridazine and
in(az)ole building blocks (X ¼ CH or N, Y ¼ O or NOMe);[3] b) fused pyridopyrida-
zine inhibitor of cGMP phosphodiesterase;[2] and c) fused benzophthalazine anticancer
agent.[1] The N, N0-disubstituted diaminopyridazine core is bold.

Facile Synthesis of 3,6-Diaminopyridazine
2351
Scheme 2. Simple two-step reaction.
reported the use of 4-methoxybenzylamine as a high-boiling ammonia
surrogate for the preparation of 2,7-diamino-1,8-naphthyridine from
2-chloro-7-amido-1,8-naphthyridine.[12] In our case, substitution of
both chloro groups of 3,6-dichloropyridazine was required. By dissolving
3,6-dichloropyridazine in neat 4-methoxybenzylamine, substitution of both
chloro groups was achieved to provide the N,N0-disubstituted diamine 2.
Similar to the reported synthesis of 2,7-diamino-1,8-naphthyridine, a limit-
ation of this method is the high cost of 4-methoxybenzylamine.[12]
Recently, N,N0-bis-(4-methoxybenzyl)-pyridazine-3,6-diamine 2 has been
prepared as part of a combinatorial library of kinase inhibitor scaffolds
via palladium-catalyzed amination.[13] It should also be noted that
N,N0-dibenzyl-pyridazine-3,6-diamine (similar to 2) has been prepared by
Parrot in quantitative yield via solid-phase synthesis with resin-bound
thiophenols.[14]
In our case, 1H NMR analysis of the crude reaction mixture revealed .95%
conversion after 3 h. 4-Methoxybenzylamine hydrochloride salt was removed
by filtration with the aid of chloroform, and the organic layer was evaporated
under reduced pressure to furnish crude N,N0-bis-(4-methoxybenzyl)-pyrida-
zine-3,6-diamine 2 as a solid residue. To effect cleavage of the PMB
moieties, a mixture of ethanol and concentrated hydrochloric acid was added
to the residual solid, and the mixture was heated to reflux for 2 h. Upon
cooling to room temperature, 1-chloromethyl-4-methoxybenzene separated
out from the aqueous solution as a brown oil and was easily removed. The
hydrochloride salt of 3,6-diaminopyridazine was obtained by removal of the
water by vacuum distillation. 3,6-Diaminopyridazine was obtained after depro-
tonation using a basic ion-exchange resin.[10] We are currently investigating the
use of 3,6-diaminopyridazine in supramolecular systems.
EXPERIMENTAL
3,6-Diaminopyridazine (3)
4-Methoxybenzylamine (11.03 g, 80.4 mmol, 4 eq.) was added to a flask
charged with 3,6-dichloropyridazine 1 (3.00 g, 20.1 mmol, 1 eq.). The
reaction mixture was placed under N2 and stirred at 1658C for 3 h before

2352
L. Xing et al.
being removed from the heating bath and allowed to reach 708C. CHCl3
(50 mL) was carefully added, and the mixture was refluxed for an additional
10 min to disperse the reagents and products. The solution was allowed to cool
to room temperature and was filtered to remove 4-methoxybenzylamine
hydrochloride as a white crystalline solid. CHCl3 was evaporated under
vacuum to yield crude 2 as a brown solid. EtOH (20 mL) and concentrated
HCl (40 mL) were added to this solid, and the resulting solution was
refluxed for 2 h. When cooled to room temperature, a brown oil that
adhered to the inside of the flask separated from the aqueous phase. The
aqueous phase was decanted into a round-bottom flask and distilled to
dryness (the acid was neutralized by an aqueous sodium hydroxide trap).
The resulting brown crystals were dissolved in water (100 mL) and washed
with CHCl3. The aqueous phase was concentrated under vacuum to ca.
30 mL, EtOH (15 mL) was added, and the solution was loaded on a column
of strongly basic ion-exchange resin (Amberlite IRA-400) and eluted with a
mixture of water/EtOH (2:1). The solvent was then removed under vacuum
to yield 1.73 g of 3 as yellow needle-like crystals (78%), which were
further purified by recrystallization from EtOH.
Rf ¼ 0.4 (CHCl3/MeOH 6:4); mp ¼ 226–2288C (lit. 235–237 8C[7,9,10]);
1H NMR (300 MHz, DMSO-d6): d ¼ 6.63 (s, 2H), 5.34 (s, 4H); 13C NMR
(75 MHz, DMSO-d6): d ¼ 154.6, 117.8, ESI MS: m/z calcd. for [M þ H]þ:
calcd: 111.067; found: 111.064. C4H6N4 (110.1) calcd.: C, 43.6; H, 5.49; N,
50.9; found: C, 43.6; H, 5.29; N, 50.5.
N,N0-Bis-(4-methoxybenzyl)-pyridazine-3,6-diamine (2)
The identity of 2 was verified after purifying crude 2 (prepared as described
previously) by silica-gel chromatography (CHCl3/MeOH 9:1). Rf ¼ 0.5
(CHCl3/MeOH 9:1); mp ¼ 132–1348C; 1H NMR (300 MHz, CDCl3):
d ¼ 7.25 (d, J ¼ 8.4 Hz, 4H), 6.84 (d, J ¼ 8.4 Hz, 4H), 6.54 (s, 2H), 4.63
(s-br, 2H), 4.43 (s, 4H), 3.75 (s, 6H), 13C NMR (75 MHz, CDCl3):
d ¼ 158.8, 154.2, 131.6, 129.1, 118.2, 114.0, 55.3, 46.0; ESI MS: m/z
calcd. for [M þ H]þ: 351.182; found: 351.185.
ACKNOWLEDGMENTS
The authors are grateful to Concordia University and Queen’s University,
Natural Sciences and Engineering Research Council [Canada] (NSERC),
´ ´
Ministry of Research and Innovation [Ontario] (MRI), Le Fonds quebecois
de la recherche sur la nature et les technologies (FQRNT), and Canada Foun-
dation for Innovation (CFI) for funding, to S. Zimmerman for valuable discus-
sions, and to Michael J. Krische for useful suggestions and proofreading the
manuscript.

Facile Synthesis of 3,6-Diaminopyridazine
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