A novel and convenient protocol for synthesis of pyridazines

Article abstract of DOI:10.1021/ol802432z

(Chemical Equation Presented) A new flexible strategy for the synthesis of diversely functionalized pyridazines from 4-chloro-1,2-diaza-1,3-butadienes and active methylene compounds is reported. The high chemoselectivity of this approach offers access to

Full text of DOI:10.1021/ol802432z

ORGANIC
LETTERS
2009
Vol. 11, No. 2
309-312
A Novel and Convenient Protocol for
Synthesis of Pyridazines
Orazio A. Attanasi, Gianfranco Favi,* Paolino Filippone, Francesca R. Perrulli,
and Stefania Santeusanio
Istituto di Chimica Organica, UniVersita` degli Studi di Urbino “Carlo Bo”, Via I
Maggetti 24, 61029 Urbino, Italy
gianfranco.faVi@uniurb.it
Received October 27, 2008
ABSTRACT
A new flexible strategy for the synthesis of diversely functionalized pyridazines from 4-chloro-1,2-diaza-1,3-butadienes and active methylene
compounds is reported. The high chemoselectivity of this approach offers access to structural precursors of GABA-A antagonist analogues.
The pyridazine1 ring is recurrent as a structural component
of biologically active compounds.2 Moreover, pyridazines
are useful intermediates in the construction of several other
heterocycles3 and in physical organic chemistry4 and recently
have been explored as new R-helix mimetics.5
The 3-aminopyridazine unit has proven to be interesting from
a pharmacological point of view.6-9 For example, Minaprine
(3) (a) Ellis, G. P. In Synthesis of Fused Heterocycles; John Wiley and
Sons Inc.: New York, 1987; pp 226-239. (b) Naud, S.; Pipelier, M.; Viault,
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81, 4342–4346. (b) Wijnen, J. W.; Zavarise, S.; Engberts, J. B. F. N.;
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30–84. (c) Sauer, J. In ComprehensiVe Heterocyclic Chemistry II; Pergamon:
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Schmitt, M. Curr. Org. Chem. 2006, 10, 277–295. For representative
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Org. Chem. 1995, 60, 748–750. (f) Helm, M. D.; Moore, J. E.; Plant, A.;
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10.1021/ol802432z CCC: $40.75
Published on Web 12/15/2008
2009 American Chemical Society

1 (Cantor) is a psychotropic drug presently used as an
antidepressant.7 Various 3-aminopyridazine derivatives of
γ-aminobutyric acid act as selective GABA-A receptor
antagonists.8,9 In particular, the 6-aryl-3-aminopyridazine
derivative of GABA, SR 95103 [2-(3-carboxypropyl)-3-
amino-4-methyl-6-phenylpyridazinium chloride], showed
high specificity and potency.9 Our synthetic efforts toward
these and related compounds have focused on the preparation
of diversely functionalized 6-aryl (alkyl)-3-aminopyridazine
derivatives.
fragment C to the active methylene compounds containing
cyano group E. In the synthetic direction, we envision the
C(4)-C(5) junction first to be installed via a Michael-type
addition of R-CH2-acidic cyano compounds with chloro-1,2-
diaza-1,3-butadienes, followed by completion of the hetero-
cycle via an internal nucleophilic ring closure. Importantly,
this proposed approach would directly place the requisite
amino group in position 3 of the pyridazine nucleus.
Because most approaches to these heterocycles suffer from
many disadvantages, including inconvenient operations, a
limited number of suitable substrates, harsh reaction conditions,
a high number of steps, and poor yields, the development of
mild and efficient methods for their synthesis is highly desirable.
Effectively, the common five-step strategy for the construction
of 6-phenyl-3-aminopyridazines10 involves synthesis of the
pyridazinone core based on the condensation of acetophenone
with R-ketoester and requires ammonia or hydrazine as a
precursor of the amino function.7c,10a
Scheme 1. Retrosynthetic Analysis of 1-Aminopyridazine A
The presence of a leaving group on the C4 of the azo-ene
skeleton plays a crucial role in the outcome of the reaction.
In fact, the key step of these reactions resides in the formation
of the R,ꢀ-unsatured hydrazones as a result of HX elimina-
tion. It should be noted that these reactions constitute an
umpolung of the classical carbonyl reactivity, since neutral
1,2-diaza-1,3-butadienes enable analogous nucleophilic ad-
ditions at the R hydrazone functionality that corresponds to
the C4 carbon of azo-ene systems.
Surprisingly, there are relatively few reports on employ-
ment of 4-chloro-1,2-diaza-1,3-butadienes in organic syn-
thesis.13 For example, South et al. reported that haloazodienes
reacted in an inverse electron demand Diels-Alder reaction
with enamines to provide tetrahydropyridazine derivatives.13e,g
In 1981, Gilchrist found that ꢀ-chloroazoalkenes reacted with
1,3-dicarbonylcompoundstoyieldfirsttheaddition-elimination
products and then pyrroles when an excess of CH2-acidic
substrate was used.13a Because of these results and of our
interest in certain 3-aminopyridazine targets, we set out to
establish reaction conditions and/or substrates that would
provide the desired 3-aminopyridazines on the basis of our
current working hypothesis.
Figure 1. Structures of some pharmaceutically important 3-aminopy-
ridazine derivatives: Minaprine 1, Gabazine 2, and SR 95103 3.
Our analysis of the 3-aminopyridazine target A (Scheme 1)
emphasizes two strategic disconnections of the pyridazine ring,
along the two carbon-carbon bonds C(4)-C(5) and C(6)-N(1).
This unveils two subunits that trace the left half back to the
hydrazone cation B and the right half to the cyano compound
frame C. Our experience in the heterocyclic constructs entices
us to correlate fragment B to the azo-ene systems D11,12 and
(8) (a) Melikian, A.; Schlewer, G.; Hurt, S.; Chantreux, D.; Wermuth,
C. G. J. Labelled Compd. Radiopharm. 1986, 24, 267–274. (b) Wermuth,
C. G.; Bizie`re, K. Trends Pharmacol. Sci. 1986, 421–424. (c) Heaulme,
M.; Chambon, J. P.; Leyris, R.; Molimard, J.-C.; Wermuth, C. G.; Bizie`re,
K. Brain Res. 1986, 384, 224–231. (d) Heaulme, M.; Chambon, J. P.; Leyris,
R.; Wermuth, C. G.; Bizie`re, K. J. Neurochem. 1987, 48, 1677–1686. (e)
Melikian, A.; Schlewer, G.; Chambon, C. G. J. Med. Chem. 1992, 35, 4092–
4097.
(11) For a review on the chemistry of 1,2-diaza-1,3-butadienes, see: (a)
Attanasi, O. A.; De Crescentini, L.; Filippone, P.; Mantellini, F.; Santeu-
sanio, S. ArkiVoc 2002, xi, 274–292.
(12) For some selected articles on the chemistry of 1,2-diaza-1,3-
butadienes, see: (a) Boeckman, R. K., Jr; Ge, P.; Reed, J. E. Org. Lett.
2001, 3, 3651–3653. (b) Kramp, G. J.; Kim, M.; Gais, H.-J.; Vermeeren,
C. J. Am. Chem. Soc. 2005, 71, 17910–17920. (c) Palacios, F.; Aparicio,
D.; Lo´pez, Y.; de los Santos, J. M. Tetrahedron 2005, 61, 2815–2830. (d)
Attanasi, O. A.; Davoli, P.; Favi, G.; Filippone, P.; Forni, A.; Moscatelli,
G.; Prati, F. Org. Lett. 2007, 9, 3461–3464. (e) Attanasi, O. A.; Favi, G.;
Filippone, P.; Giorgi, G.; Mantellini, F.; Moscatelli, G.; Spinelli, D. Org.
Lett. 2008, 10, 1983–1986.
(9) (a) Bourguignon, J.-J.; Schlewer, G.; Melikian, A.; Chantreux, D.;
Molimard, J.-C.; Heaulme, M.; Chambon, J.-P.; Biziere, K.; Wermuth, C. G.
Pharmacologist 1985, 27518s(b) Chambon, J. P.; Felz, P.; Heaulme, M.;
Restle´, S.; Schlichter, R.; Bizie`re, K.; Wermuth, C. G. Proc. Natl. Acad.
Sci. U.S.A. 1985, 82, 1832–1836. (c) Wermuth, C. G.; Bourguignon, J.-J.;
Schlewer, G.; Gies, J.-P.; Schoenfelder, A.; Melikian, A.; Bouchet, M.-J.;
Chantreux, D.; Molimard, J.-C.; Heaulme, M.; Chambon, J.-P.; Biziere, K.
J. Med. Chem. 1987, 30, 239–249.
(13) (a) Gilchrist, T. L.; Parton, B.; Stevens, J. A. Tetrahedron Lett.
1981, 22, 1059–1062. (b) Gilchrist, T. L.; Stevens, J. A. J. Chem. Soc.,
Perkin Trans. 1985, 1, 1741–1745. (c) South, M. S.; Jakuboski, T. L.
Tetrahedron Lett. 1995, 36, 5703–5706. (d) South, M. S.; Jakuboski, T. L.;
Westmeyer, M. D.; Dukesherer, D. R. Tetrahedron Lett. 1996, 37, 1351–
1354. (e) South, M. S.; Jakuboski, T. L.; Westmeyer, M. D.; Dukesherer,
D. R. J. Org. Chem. 1996, 61, 8921–8934. (f) South, M. S. J. Heterocycl.
Chem. 1999, 36, 301–319. (g) Attanasi, O. A.; Favi, G.; Filippone, P.;
Golobicˇ, A.; Perrulli, F. R.; Stanovnik, B.; Svete, J. Synlett 2007, 2971–
2974.
(10) For synthesis of 3-aminopyridazines, see: (a) Sitamze, J.-M.;
Schmitt, M.; Wermuth, C. G. J. Org. Chem. 1992, 57, 3257–3258. (b)
Rykowski, A.; Wolin˜ska, E. Tetrahedron Lett. 1996, 37, 5795–5796. (c)
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Org. Lett., Vol. 11, No. 2, 2009

nitrile 2c, malononitrile 2d, and benzensulfonilacetonitrile
2e reacted with 1b to form the corresponding R,ꢀ-unsatured
hydrazone 3a-c in good yields (entries 3-5). More pre-
cisely, the reaction furnished crude product 3a-c by direct
precipitation from the reaction mixture. To obtain the
respective pyridazine 4c-e, the same intermediates 3a-c
were subjected to intramolecular ring closure in the presence
of a stoichiometric amount of sodium methoxide (CH3ONa)
in methanol (CH3OH) at reflux (Table 1).
Table 1. Michael-Type Addition/Heterocyclization of Active
Methylene Cyano Compounds 2a-f on 1,2-Diaza-1,3-butadienes
1a,b;a Syntheses of 3-Aminopyridazines 4a-f
Interestingly, even 4-nitrophenylacetonitrile 2f having in
the R-position only a single carbonyl group reacted efficiently
with 1a to afford the respective addition-elimination product
3d (entry 6). As expected, the latter hydrazone 3d was an
effective substrate, giving 4f in excellent yield.
In light of the latest results, we next decided to explore
the full potential of this methodology using a variety of
structurally diverse active methylene compounds (Table 2,
entries 1-8).
Active methylene compounds containing ketone groups
such as acetylacetone 2g, cycloexane-1,3-dione 2h, ethyl
acetoacetate 2i, acetoacetanilide 2j, p-acetoacetanisidide 2k,
4-chlorophenylsulfonylacetone 2l, p-toluensulfonylacetone
2m and 4-nitrophenylacetone 2n reacted with 1a,b to give
the corresponding R,ꢀ-unsatured hydrazones 3e-f or py-
ridazine derivatives 4g-j,l,m in high yields (entries 1-8).
Following the same heterocyclization process mediated by
sodium methoxide (CH3ONa), we were able to obtain
pyridazines 4k,n in good yields (Table 2).
Among these pyridazine compounds 4g-n, tetrahydro-
cynnoline derivative 4h proved to be reversible inhibitors
of monoamine oxidase (MAO-A and MAO-B).15 This fact
confers an extra contribution of our methodology toward
synthesis of pharmacologically active molecules.
Only in the case of the reaction between 1a and 2i, the
desired cyclization of the amide to the ketone was competing
with the ring closure on the ester group, giving pyridazinone
(see 5a in Supporting Information) as a substantial byproduct
(11% yield). Finally, applying the same procedure to
dimethyl malonate resulted in a complicated crude mixture
from which only a low yield of the R,ꢀ-unsaturated hydra-
zone was isolated.
a All reactions were carried out in CHCl3 (5 mL) at rt for 1-24 h using
1,2-diaza-1,3-butadienes 1a,b (1.0 mmol), active methylene compounds
2a-f (1.0 mmol), and DIPEA (1.1 mmol) (TLC check). b Yields of isolated
product by crystallization. c Isolated yield after silica gel chromatography.
d All reactions were carried out under reflux for 3-6 h by treatment of
3a-d (0.5 mmol) in MeOH (10 mL) with MeONa (0.5 mmol) (TLC check).
As a first approach to compound 4a, the 4-chloro-1,2-
diaza-1,3-butadiene 1a, possessing an aminocarbonyl moiety
on N(1), was reacted with the commercially available methyl
cyanoacetate 2a to give exclusively 3-aminopyridazine (4a)
in 80% yield (Table 1, entry 1).
Fortunately, from this reaction we did not observe any
bis-addition product or pyrrole derivative, contrary to what
was previously reported by Gilchrist. The presence of an
aminocarbonyl residue instead of an alkoxycarbonyl (or aryl)
on the N(1) of the azo-ene system is essential for the
pyridazine ring formation, showing the intrinsic preference
of this group to the heterocyclization process. A brief study
revealed optimized reaction conditions: CHCl3 as solvent,
room temperature, and DIPEA as base (1.1 equiv).
Under the above-mentionated conditions, a range of active
methylene compounds 2a-f containing a cyano group were
tested in Michael additions with 4-chloro-1,2-diaza-1,3-
butadienes 1a,b14 (Table 1, entries 1-6).
In such reactions, the active methylene compound fur-
nishes only two ring atoms (CsC), while the 1,2-diaza-1,3-
butadiene partner provides the remaining four heteroring
atoms (CsCsNsN) to the final pyridazine.
It should be noted that amino, ketone, ester, cyano, sulfone,
amide, and aryl groups were all tolerated, providing the
corresponding pyridazines in good to high yields. While
many of the known methods are often incompatible with
various functional groups or general substitution patterns,
the present approach proves quite general. However, the
products could be of great interest for the synthesis of many
other complex heterocyclic templates.
On the basis of the obtained results, a plausible mechanism
for the synthesis of variously functionalized pyridazine 4 is
hypothesized (Scheme 2).
The transformation starts from the base-promoted attack of
the active carbon atom of 2 at the terminal carbon of the azo-
The ethyl cyanoacetate 2b also worked well to give
analogous 3-aminopyridazine 4b (entry 2). 2-Thenoylaceto-
(14) 1,2-Diaza-1,3-butadienes 1a,b were synthesized from the corre-
sponding dichlorohydrazones by treatment with base (see Supporting
Information).
Org. Lett., Vol. 11, No. 2, 2009
311

Table 2. Michael-Type Addition/Heterocyclization of Active
Methylene Ketones Compounds 2g-n on
Scheme 2. Mechanisms for the Formation of Pyridazines 4a-n
1,2-Diaza-1,3-butadienes 1a,b;a Syntheses of Pyridazines 4g-n
It is important to note that the success of this pathway
depends on the nature of moiety bonded to the terminal
carbon atom of azo-ene system. In fact, in the six-membered
heterocycle formation only an “external” amidic nitrogen
atom can be operative with “closing” groups on the attacking
nucleophiles, thus prohibiting a possible five-membered ring
closure to give pyrrole derivatives. On the contrary, this latter
behavior was observed when 4-alkoxy (or dialkylamino)-
carbonyl-1,2-diaza-1,3-butadienes have been employed.11
In summary, a new (base-mediated, metal-free) and efficient
synthesis yielding pyridazines 4 from readily available 4-chloro-
1,2-diaza-1,3-butadienes 1 and active methylene compounds 2
has been developed. This protocol is especially attractive as it
allows for the preparation of variously functionalized py-
ridazines in one or two steps. Moreover, the high chemoselec-
tivity of this strategy offers access to structural precursors of
GABA-A antagonist analogues (3-aminopyridazine derivatives)
if practiced on a substrate bearing a cyano substituent (EWG
) CN). The ease of construction of pyridazines and the broad
availability of active methylene compounds implies that an
extensive range of substituents/functionalities can be directly
incorporated in the pyridine ring, making this procedure
particularly useful for the preparation of libraries.
a All reactions were carried out in CHCl3 (5 mL) at rt for 1-24 h using
1,2-diaza-1,3-butadienes 1a,b (1.0 mmol), active methylene compounds
2g-n (1.0 mmol), and DIPEA (1.1 mmol) (TLC check). b Yields of isolated
product by crystallization. c Isolated yield after silica gel chromatography.
d All reactions were carried out under reflux for 3-6 h by treatment of 3e,f
(0.5 mmol) in MeOH (10 mL) with MeONa (0.5 mmol) (TLC check).
e Pyridazinone 5a (see Supporting Information) was also isolated in 11%
yield after silica gel chromatography.
ene system of 1 (Michael-type addition) to generate an adduct
intermediate (I) followed by a dehydroalogenation reaction to
give more stable R,ꢀ-unsaturated hydrazone 3. Subsequently,
an intramolecular aza-cyclization of 3 by a nucleophilic attack
of the carbamic nitrogen atom on a nitrile or carbonyl function
results in the formation of a diyhdropyridazine ring (II). The
spontaneous loss of carbamic residue resulting from the base-
induced hydrolysis and decarboxylation (intermediate III) with
consequent elimination of a water molecule (for 4g-n) or NH/
NH2 tautomerism (for 4a-f) leads to pyridazine compound 4.
Acknowledgment. This work was supported by the
financial assistance from the Ministero dell’Istruzione,
dell’Universita` e della Ricerca (MIUR) Roma and Universita`
degli Studi di Urbino “Carlo Bo”.
Supporting Information Available: Experimental pro-
cedures and full characterization for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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Thull, U.; Carrupt, P.-A.; Testa, B.; Stoeckli-Evans, H. J. Med. Chem. 1998,
41, 3812–3820.
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