Polysubstituted pyridazinones from sequential nucleophilic substitution reactions of tetrafluoropyridazine

Article abstract of DOI:10.1021/jo9006943

(Chemical Equation Presented) 4,5,6-Trifluoropyridazin-3(2H)-one can be used as a scaffold for the synthesis of various 4,5- and 4,6-disubstituted and ring-fused pyridazinone systems by sequential nucleophilic aromatic substitution processes. Although the

Full text of DOI:10.1021/jo9006943

pubs.acs.org/joc
Polysubstituted Pyridazinones from Sequential Nucleophilic Substitution
Reactions of Tetrafluoropyridazine
Graham Pattison,† Graham Sandford,*,† Dmitry S. Yufit,‡ Judith A. K. Howard,‡
John A. Christopher,§ and David D. Miller§
‡
†Department of Chemistry and Chemical Crystallography Group, Department of Chemistry,
Durham University, South Road, Durham DH1 3LE, U.K., and GlaxoSmithKline R&D, Medicines
Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
§
graham.sandford@durham.ac.uk
Received April 23, 2009
4,5,6-Trifluoropyridazin-3(2H)-one can be used as a scaffold for the synthesis of various 4,5- and 4,6-
disubstituted and ring-fused pyridazinone systems by sequential nucleophilic aromatic substitution
processes. Although the regioselectivity of nucleophilic substitution can be affected by the nature of
the nucleophile and the substituent attached to the pyridazinone ring, a variety of polyfunctional
systems can be readily accessed by sequential nucleophilic substitution methodology which may have
applications in the drug discovery arena. For example, reaction of 4,5,6-trifluoropyridazin-3(2H)-
one with nitrogen nucleophiles leads to a mixture of aminated products arising from substitution of
fluorine located at the 4- and 5-positions. The ratio of isomers obtained depends on the nucleophile
where the 4-isomer is the major product for reaction with primary and secondary amines such as
butylamine, morpholine, and aniline derivatives. Subsequent reaction of representative 4-aminated
products gave 4,5-disubstituted systems and ring fused derivatives may be formed by reaction of
4,5,6-trifluoropyridazin-3(2H)-one or 4-substituted systems with N,N0-dimethylethylenediamine.
Introduction
toxicity; ADME-Tox) parameters.4 Various approaches to
predict drug-likeness have been developed in recent years
including simple counting schemes, functional group meth-
ods and analysis of the multidimensional “chemical space”
occupied by drugs.5,6
In one popular approach, Lipinski outlined some “conser-
vative predictors”7,8 of the types of properties thatmany drug-
like systems must possess in order to aid medicinal chemists in
selecting synthetic target molecules. This approach aims to
help reduce compound attrition rates during the more re-
source intensive clinical stages of drug development programs
and limit the use of resources on the synthesis of molecules
that do not have useful “drug-like” characteristics.
Although high-throughput screening (HTS) and parallel
synthesis techniques have seen increasing use in recent years,
allowing large numbers of compounds to be synthesized and
assessed for biological activity by a variety of in vitro assays
within a very short time frame,1 the number of suitable new
chemical entities developed by the pharmaceutical industry
for hit-to-lead generation has been relatively disappointing
over the past decade.2,3 Consequently, much attention has
been focused upon the development of predictive tools that
can recognize “drug-like” molecular entities that may pro-
vide guidance to medicinal chemists in their choice of
synthetic target molecules. In general, molecular “drug-like”
properties can be defined as being a combination of favor-
able physiochemical (e.g., solubility, stability) and biological
(e.g., absorption, distribution, metabolism, elimination and
Many rigid, heteroaromatic systems fall within the Lipinski
parameters, and it is estimated that approximately 70%
of all commercially successful pharmaceuticals possess a
(4) Sugiyama, Y. Drug Discovery Today 2005, 10, 1577–1579.
(5) Walters, W. P.; Murcko, A.; Murcko, M. A. Curr. Opin. Chem. Biol.
1999, 3, 384–387.
(6) Walters, W. P.; Murcko, M. A. Adv. Drug Delivery Rev. 2002,54, 255–271.
(7) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv.
Drug Delivery Rev. 2001, 46, 3–26.
*To whom correspondence should be addressed. Tel: +44(0)1913342039.
Fax: +44(0)1913844737.
(1) Patel, D. V.; Gordon, E. M. Drug Discovery Today 1996, 1, 134–144.
(2) Leach, A. R.; Hann, M. M. Drug Discovery Today 2000, 5, 326–336.
(3) Bailey, D.; Brown, D. Drug Discovery Today 2001, 6, 57–59.
(8) Lipinski, C. A. Drug Discov. Today: Technol. 2004, 1, 337–341.
DOI: 10.1021/jo9006943
r
Published on Web 06/11/2009
J. Org. Chem. 2009, 74, 5533–5540 5533
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Pattison et al.
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heterocyclic subunit within their structures. A core heteroaro-
matic scaffold presents a diverse range of substituents in a
well-defined three-dimensional space which may effectively
bind at appropriate receptor sites.
There exists, therefore, a continuing requirement in the life
science industries for accessible, novel, heterocyclic scaffolds
that bear multiple functionality and can be readily processed
into systems that possess maximally diverse structural fea-
tures to significantly increase the chances of generating new
“lead” compounds for subsequent development. In order to
be useful, heterocyclic “core scaffolds” must bear several
reactive sites that may be readily functionalized in a regio-
controlled manner in high yield, but unfortunately, scaffold
and subsequent analogue syntheses of many polyfunctiona-
lized heterocyclic systems are hampered by the inherent low
reactivity of many aromatic heterocyclic systems.9,10
An emerging approach that aims to provide a solution to
the problem of regioselective polyfunctionalization of het-
eroaromatic systems from simple, readily available core
scaffolds involves sequential regioselective nucleophilic aro-
matic substitution of perfluorinated heteroaromatic precur-
sors,11 such as pentafluoropyridine, which have been used as
the starting material for the synthesis of various multisub-
stituted pyridine derivatives with useful biological activity.12
Various systems synthesized from highly fluorinated hetero-
aromatic systems are biologically active, and for example,
several validated targets in the search for novel antithrom-
botic drugs have been synthesized by sequential substitution
processes from pentafluoropyridine.13-15 Furthermore, re-
action of pentafluoropyridine with various difunctional
nucleophiles has led to a range of bicyclic heteroaromatic
scaffolds16-18 which act as precursors for the synthesis of, for
example, a number of functionalized imidazopyridine ana-
logues.19
FIGURE 1. Pyridazinone-based life science products.
tetrafluoropyridazine in concentrated sulfuric acid,20 no
reactions of this potentially very versatile scaffold have been
published.
Of particular relevance to the chemistry described in this
paper, pyridazinone structural units are present in a wide
range of commercially important drugs and agrochemicals
such as the antiplatelet clotting agent Zardaverine, the anti-
inflammatory Emorfazone,21 the COX-2 inhibitor ABT-
963,22 as well as the herbicide Norflurazon (Figure 1).
In general, pyridazinones are synthesized by condensation
of 1,4-dicarbonyl compounds with hydrazines23 or by Car-
boni-Lindsey cycloaddition reactions.24 However, both of
these routes can suffer from poor yields and are generally
inflexible, with substituent groups remaining limited to those
that are present in the initial starting materials. Recent
approaches to the synthesis of pyridazinone analogues
have involved palladium-catalyzed Suzuki coupling pro-
cesses,25-27 nucleophilic aromatic substitution28 reactions of
As part of our continuing studies concerning the use of
perfluoroheteroaromatic systems as scaffolds for the drug
discovery process, we envisaged that successive nucleophilic
displacements using 4,5,6-trifluoropyridazin-3(2H)-one as
the starting scaffold would allow us to produce a variety of
polysubstituted pyridazinones by flexible methodology
that would be applicable to parallel synthesis techniques.
While 4,5,6-trifluoropyridazin-3(2H)-one has been synthe-
sized previously by hydrolysis of the commercially available
(9) Katritzky, A. R.; Rees, C. W. Comprehensive Heterocyclic Chemistry;
Pergamon Press: Oxford, 1984.
(10) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles; Thieme:
Stuttgart, 1995.
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Soc. C 1968, 2989–2994.
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(12) Cartwright, M. W.; Christopher, J. A.; Miller, D. D.; Sandford, G.;
Slater, R.; Smith, P. W.; Vong, A. Chim. Oggi 2007, 25, 40–44.
(13) Ng, H. P.; Buckman, B. O.; Eagen, K. A.; Guilford, W. J.;
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A.; Ho, L. T. E.; Smith, D.; Subramanyam, B.; Vergona, R.; Walters, J.;
White, K. A.; Sullivan, M. E.; Morrissey, M. M.; Phillips, G. B. Biorg. Med.
Chem. 2002, 657–666.
(21) DalPiaz, V.; Giovannoni, M. P.; Ciciani, G.; Barlocco, D.; Giardina,
G.; Petrone, G.; Clarke, G. D. Eur. J. Med. Chem. 1996, 31, 65–70.
(22) Kerdesky, F. A. J.; Leanna, M. R.; Zhang, J.; Li, W. K.; Lallamann,
J. E.; Ji, J. G.; Morton, H. E. Org. Proc. Res. Dev. 2006, 10, 512–517.
(23) Zhang, J.; Morton, H. E.; Li, J. G. Tetrahedron Lett. 2006, 47, 8733–
8735.
(24) Saracoglu, N. Tetrahedron 2007, 63, 4199–4236.
(14) Kranjc, A.; Kikelj, D.; Peterlin-Masic, L. Curr. Pharm. Des. 2005,
11, 4207–4227.
(15) Walenga, J. M.; Jeske, W. P.; Hoppensteadt, D.; Fareed, J. Curr.
Opin. Investig. Drugs 2003, 4, 272–281.
(16) Sandford, G.; Slater, R.; Yufit, D. S.; Howard, J. A. K.; Vong, A. J.
Org. Chem. 2005, 70, 7208–7216.
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E.; Rozenski, J.; Dommisse, R. A.; Haemers, A. Tetrahedron 2001, 57, 1323–
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Vong, A. J. Org. Chem. 2005, 70, 9377–9381.
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J. A. K.; Vong, A. Tetrahedron 2007, 63, 5204–5211.
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J. A. K.; Christopher, J. A.; Miller, D. D. Tetrahedron 2007, 63, 7027–7035.
(27) Monsieurs, K.; Tapolcsanyi, P.; Loones, K. T. J.; Neumajer, G.;
Ridder, J. A. D. D.; Goubitz, K.; Lemiere, G. L. F.; Dommisse, R. A.;
Matyus, P.; Maes, B. U. W. Tetrahedron 2007, 63, 3870–3881.
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TABLE 1. Reactions of 4,5,6-Trifluoropyridazin-3(2H)-one 1 with Nucleophiles
a Isolated yields after column chromatography/recrystallization. b Ratios measured by integration of 19F NMR spectrum of crude reaction mixture.
* Not isolated.
dihalogenated pyridazinones, or cycloaddition reactions
of tetrazines with alkynyl boronate derivatives29 which
sometimes allow greater flexibility in substituent introduction
but, in many cases, result in poor regioselectivities.
In this paper, we describe our studies concerning suc-
cessive nucleophilic aromatic substitution reactions of
4,5,6-trifluoropyridazin-3(2H)-one in order to establish the
(29) Helm, M. D.; Plant, A.; Harrity, J. P. A. Org. Biomol. Chem. 2006, 4,
4278–4280.
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TABLE 2. Reaction of 4-Morpholino-5,6-difluoropyridazin-3(2H)-one 2g
with Amines
SCHEME 1. Synthesis and Molecular Structure of 4,5,6-Tri-
fluoropyridazin-3(2H)-one 1
procedure20 and further characterized here by X-ray crystal-
lography (see the Supporting Information), which showed that
1 exists as the CdO tautomer in the solid state as deduced from
ꢀ
˚
the short CdO bond length (1.233 A).
Reaction of 4,5,6-trifluoropyridazin-3(2H)-one with a
series of nitrogen-centered nucleophiles resulted in mixtures
of products arising from substitution at the 4- and 5-posi-
tions of the pyridazinone ring (Table 1).
Primary amines were relatively unselective in their reac-
tion with 1, the highest selectivity observed being 61:39 in
favor of the 4-isomer when benzylamine was used as the
nucleophile. However, in each case, the two isomers 2 and 3
produced by displacement of the 4- and 5-fluorine substitu-
ents of 1, respectively, were readily separable by column
chromatography for the majority of cases (Table 1). Second-
ary amines were more selective, producing both 4- and
5- substituted isomers in a ratio of approximately 3:1 in each
case while, in contrast, less reactive nucleophiles, such as
aniline, gave a higher degree of regioselectivity with a ratio of
up to 96:4 favoring the 4- substituted isomer.
The identity of the 4-benzylamino 2c, 4-piperidine 2f,
and 5-butylamino 3b products were confirmed by X-ray
crystallography (see Supporting Information) and all other
4- and 5-substituted pyridazinone products were identified
by comparison of NMR data with the spectra obtained from
2c and 3b.
We would expect the 4- and 5-positions in 1 to be the
most activated sites toward nucleophilic attack. Position
4 is para to ring nitrogen, which is highly activating,
and ortho and meta to ring fluorine which are also activat-
ing, as determined by well-established kinetic data.11
Position 5 is also activated by ring nitrogen and two
fluorine atoms that are located ortho to this site. In this
case, the results shown in Table 1 demonstrate that mix-
tures of products arising from substitution at either the
4- or 5-position are indeed obtained under the reaction
conditions employed, and in general, “softer”, less reac-
tive, nitrogen-centered nucleophiles such as aniline deri-
vatives favor substitution at the “softer” 4- position which
is ortho to CdO and C-F bonds, rather than two C-F
bonds. It appears that since oxygen is not significantly less
electronegative than fluorine, small changes in nucleophi-
lic character have an effect on the regioselectivity of these
nucleophilic aromatic substitution processes under the
reaction conditions utilized.
Unfortunately, reactions of trifluoropyridazinone with
various alkoxide salts or sterically hindered secondary
amine nucleophiles, such as diisopropylamine or 2,2,6,6-
tetramethylpiperidine, gave intractable tars. The exact
pathway of decomposition is unclear, but these results
demonstrate that reactions of trifluoropyridazinone are
limited to nucleophiles of relatively low basicity and high
nucleophilicity.
reactivity profile of this system and determine whether this
scaffold could be used for the synthesis of many pyridazi-
none analogues offering new methodology for the synthesis
of polyfunctional pyridazinone systems that are very difficult
to access by established synthetic procedures.
Results and Discussion
4,5,6-Trifluoropyridazin-3(2H)-one (1) was prepared in
high yield (Scheme 1) from commercially available tetra-
fluoropyridazine and sulfuric acid following the literature
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TABLE 3. Reactions of 4-Morpholino-5,6-difluoropyridazin-3(2H)-one (2g) with Alkoxides
a Yields isolated after mass-directed HPLC. b Isomer ratios determined by integration of crude 19F NMR spectra.
SCHEME 2. Reaction of 2g with 4-Bromoaniline
With these results in hand, we studied model reactions
of representative pyridazinones, the 4-morpholino- (2g),
4-bromoanilino- (2j), and 4-butylaminodifluoropyridazi-
none (2b) derivatives, respectively, with a range of primary,
secondary, and aryl amines, alkoxides, phenoxides, and
thiolates under microwave irradiation conditions in order
to establish whether these difluorinated systems could be
used as scaffolds for further functionalization through nu-
cleophilic displacement of the remaining two fluorine atoms.
5,6-Difluoro-4-morpholinopyridazin-3(2H)-one (2g) re-
acted efficiently with a range of primary and secondary
amine nucleophiles, yielding products that arise from selec-
tive substitution at the 5-position. Yields after recrystalliza-
tion were reasonable (Table 2), except in the case of
diethylamine, which showed only moderate conversion
(70% after 1 h irradiation at 150 °C), and this reflects the
increased steric demand of the nucleophile.
peak at -90 to -100 ppm attributed to F-6 of the mono-
fluorinated pyridazinone product. In these reactions, sub-
stitution occurs at the site para to ring nitrogen as would be
expected.
Less reactive aniline derivatives did not react with 2g
unless the corresponding sodium salt was used. In this case,
a mixture of products was observed in the ratio 53: 47 by 19F
NMR analysis of the crude product mixture and mass
directed HPLC allowed the isolation of both isomers, albeit
in low isolated yield (Scheme 2).
In cases of reactions of alkoxide nucleophiles with 2g
(Table 3), poor conversion (∼50%) to the disubstituted
system was accompanied by competing substitution at the
6-position, although each regioisomer could be isolated by
mass directed HPLC techniques. It appears that for harder
nucleophiles such as sodium alkoxides, competing substitu-
tion occurs at the harder C-F site, adjacent to the ring
nitrogen.
In all cases, 19F NMR spectroscopy showed the disap-
pearance of the peak attributed to F-5 (∼-150 ppm) of the
morpholino derivative 2g and the appearance of a single
In addition, 4-(4-bromophenylamino)-5,6-difluoropyri-
dazin-3(2H)-one (2j) reacts efficiently with primary amines
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TABLE 4. Reactions of 4-(4-Bromophenylamino)-5,6-difluoropyridazin-
3(2H)-one 2j with Nucleophiles
SCHEME 3. Reactions of 2b-d
probe the reasons for the relatively low reactivity of 2c, we
obtained a crystal structure to determine whether any intra-
molecular interactions were present that may deactivate the
system. However, this revealed that there is no hydrogen bond
between the alkylamino NH and the pyridazinone CdO in the
solid state, which could, potentially, deactivate the ring
toward nucleophilic attack. Furthermore, NMR studies
showed that in the presence of an amine base, such as
diethylamine, the pyridazinone ring NH is rapidly exchanged
in solution but there no corresponding exchange of the NHBu
proton. This is also the case for the corresponding 4-morpho-
linopyridazinone system 2g which is reactive toward nucleo-
philic attack.
The lack of reactivity of 2b and 2c toward further
nucleophilic attack (Scheme 3) is most likely to be due to
the overlap of the lone pair of electrons on nitrogen of the
amine group with the pyridazinone ring which, if signifi-
cant, has an overall deactivating effect. In the case of
secondary amines and aniline derivatives, steric hindrance
between the substituent and adjacent fluorine and oxygen
atoms forces the amine lone pair out of the plane of the
pyridazinone ring preventing conjugation. To demonstrate
this effect, the corresponding 4-N-methylbutylamino deri-
vative 2d readily undergoes nucleophilic substitution
(Scheme 3) with butylamine to yield the 4,5-disubstituted
product 9.
By similar processes, the 5-substituted pyridazinone
systems obtained as minor products in Table 1 undergo
nucleophilic substitution at the 4- position (Scheme 4), for
example, 5-morpholino-4,6-difluoropyridazin-3(2H)-one
(3g), obtained as the minor product in the reaction of
trifluoropyridazin-3(2H)-one with morpholine, gave di-
substituted products upon reaction with primary and
secondary amines. Similarly, 5-butylamino-4,6-difluoro-
pyridazin-3(2H)-one (3b) is also reactive toward nucleo-
philic displacement, unlike its 4-substituted isomer,
undergoing displacement with a second equivalent of
butylamine regioselectively at the 4- position. Again, sub-
stitution occurs at the most activated sites para to ring
nitrogen as would be expected.
but in the case of secondary amines yields are only moderate
(Table 4). This is most likely to be due to the increased steric
demand of the secondary amines that hinders attack at the
site adjacent to the aniline substituent. Indeed, in the case of
a second equivalent of aniline, substitution is exclusively
directed to the less sterically hindered 6-position. Again,
yields of disubstituted products using alkoxide nucleophiles
are low due to decomposition of the starting material but less
basic thiolate salts gave excellent yields of disubstituted
pyridazinone products.
4-Butylamino-5,6-difluoropyridazin-3(2H)-one (2b) and
4-benzylamino-5,6-difluoropyridazin-3(2H)-one (2c) proved
unreactive toward further nucleophilic displacement proces-
ses (Scheme 3), even after prolonged microwave irradiation,
and at first sight, this is surprising because of the structural
similarity of these molecules to related systems. In order to
Since fluorine atoms on adjacent 4- and 5-positions are
sequentially replaced by nitrogen nucleophiles, we studied a
representative annelation reaction between 4,5,6-trifluoro-
pyridazin-3(2H)-one and N,N0-dimethylethylenediamine,
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SCHEME 4. Reactions of 5-Morpholino-4,6-difluoropyridazin-
3(2H)-one (3g)
confirmed by X-ray crystallography (see the Supporting In-
formation).
Conclusions
Trifluoropyridazin-3(2H)-one (1) can be readily synthe-
sized from commercially available tetrafluoropyridazine and
reacts with a range of amine nucleophiles to give mixtures of
4- and 5-substituted products, the 4-substituted isomer being
particularly favored in reactions with soft nucleophiles such
as aniline. In most cases, however, both regioisomers can be
readily separated by chromatography. Reactions with basic
nucleophiles such as alkoxides give complex product mix-
tures due to competing decomposition pathways. The
monoaminated derivatives can be further reacted with nu-
cleophiles to yield 4,5-disubstituted products regioselec-
tively, and overall, this methodology provides an excellent
route to 4,5-amino-6-fluoropyridazin-3(2H)-one deriva-
tives. Nonhalogenated products can be synthesized if the
final displacement step is intramolecular leading to poly-
functional ring fused systems. Consequently, the sequential
fluorine displacement methodology developed further in this
paper has great potential for the production of a wide range
of polyfunctional heteroaromatic derivatives from reaction
of highly fluorinated scaffolds with a wide variety of nucleo-
philes for application in the drug discovery process.
SCHEME 5. Synthesis of Bicyclic System 11
SCHEME 6. Ring-Fused Products 12a,b
Experimental Section
Reactions of Trifluoropyridazinone with Amines. General
Procedure. The amine was mixed with 4,5,6-trifluoropyrida-
zin-3(2H)-one under an atmosphere of dry nitrogen. Acetoni-
trile (5 mL) was added and the mixture stirred at room
temperature for 48 h. After this period, the solvent was
evaporated and the residue dissolved in dichloromethane
(10 mL). Water (10 mL) was added and the organic layer
separated. The aqueous layer was then extracted with further
portions of dichloromethane (2 ꢀ 10 mL), and the combined
organic extracts were dried (MgSO4) and evaporated. Purifica-
tion by flash column chromatography on silica gel gave pure
product.
5,6-Difluoro-4-morpholinopyridazin-3(2H)-one (2g) and 4,6-
Difluoro-5-(4-morpholinyl)-3(2H)-pyridazinone (3g). 4,5,6-Tri-
fluoropyridazin-3(2H)-one (0.50 g, 3.33 mmol), morpholine
(0.58 mL, 6.66 mmol), and acetonitrile (20 mL) gave a crude
yellow product (0.59 g). Flash column chromatography (cy-
clohexane/ethyl acetate 4:1 as elutant) gave 5,6-difluoro-4-
morpholinopyridazin-3(2H)-one (2g) (0.42 g, 59%) as white
crystals: mp 179 °C; δH (400 MHz, DMSO-d6) 3.64 (4 H, br t,
3JHH 4.5, C-20), 3.81 (4 H, t, 3JHH 4.5, C-30), 10.33 (1 H, br s, N
(2)H); δC (100 MHz, DMSO-d6) 48.8 (d, 4JCF 4.6, C-2’), 66.5
and indeed, ring-fused system 11 was prepared in high yield
after stirring at room temperature (Scheme 5).
All our attempts at displacement of the remaining fluor-
ine atom still attached to the heterocyclic ring in disub-
stituted pyridazinone derivatives proved unsuccessful, in-
dicating that the disubstituted pyridazinone ring is now not
sufficiently electrophilic for nucleophilic substitution to
occur. However, this could prove advantageous because
fluorine substituents attached to heteroaromatic rings
have been shown to impart desirable properties to drug-
like molecules, such as inhibiting metabolism, lowering
the basicity of molecules for in vivo applications and
increasing lipophilicity.
In contrast, reaction of monosubstituted pyridazinone sys-
tems 2g and 2k with the difunctional nucleophile N,N0-
dimethylethylene diamine allowed the synthesis of products
arising from displacement of all fluorine atoms from the
pyridazinone ring (Scheme 6). This enhanced reactivity is
reflected in the relative reactivity found in intramolecular
nucleophilic substitution reactions compared to corresponding
intermolecular processes. The structure of derivative 12a was
5
2
3
(d, JCF 1.7, C-30), 133.9 (dd, JCF 7.2, JCF 2.3, C-4), 137.0
1
(dd, JCF 264.8, JCF 32.7, C-5), 147.4 (dd, JCF 226.8, JCF
2
1
2
3
4
19.2, C-6), 159.8 (d, JCF 9.1, JCF 0.8, C-3); δF (376 MHz,
3
3
DMSO-d6) -109.3 (1F, d, JFF 29.5, F-6), -149.0 (1F, JFF
29.5, F-5); m/z (EI+) 217 ([M]+, 16), 132 (100). Anal. Calcd
for C8H9N3F2O2: C, 44.2; H, 4.2; N, 19.4. Found: C, 44.41; H,
4.20; N, 19.47. 4,6-Difluoro-5-(4-morpholinyl)-3(2H)-pyri-
dazinone (3g) (0.09 g, 12%) as white crystals: mp 179-
180 °C; δF (376 MHz, CDCl3) -92.0 (1 F, d, 4JFF 20.7, F-6),
-146.9 (1 F, d, 4JFF 20.7, F-4); δH (400 MHz, CDCl3) 3.42 (4
5
3
H, dt, 3JHH 5.8, JHF 2.0, H-2’), 3.81 (5 H, t, JHH 4.8, H-30,
OH); δC (100 MHz, CDCl3) 50.3 (dd, 4JCF 4.0, C-2’), 66.8 (d,
5JCF 1.6, C-30), 130.0 (dd, 2JCF 27.9, 2JCF 5.6, C-5), 145.4 (dd,
1JCF 255.6, 3JCF 12.0, C-4), 149.5 (dd, 1JCF 237.3, 3JCF 8.8, C-
6), 160.9 (d, JCF 23.2, C-3); m/z (ES+) 218 ([M+H]+, 100).
2
J. Org. Chem. Vol. 74, No. 15, 2009 5539

Pattison et al.
JOCArticle
Anal. Calcd for C8H9N3F2O2: C, 44.2; H, 4.2; N, 19.4. Found:
C, 44.23; H, 4.08; N, 19.12.
Synthesis of Ring-Fused Products
8-Fluoro-1,2,3,4-tetrahydro-1,4-dimethylpyrazino[2,3-d]pyri-
dazin-5(6H)-one (11). 4,5,6-Trifluoropyridazin-3(2H)-one (1.00 g,
6.67 mmol) was dissolved in acetonitrile (50 mL) under argon
with stirring. N,N0-Dimethylethylenediamine (1.43 mL, 13.3 mmol)
was added dropwise and the mixture stirred at room temperature
for 16 h. After this period, the solvent was evaporated and the
crude material redissolved in dichloromethane (50 mL) and water
(50 mL). The aqueous layer was separated and washed with
further portions of dichloromethane (3 ꢀ 25 mL). The combined
organic extracts were dried (MgSO4), filtered, and evaporated in
vacuo to yield a crude yellow product (1.08 g), which was purified
by recrystallization from acetonitrile to yield 8-fluoro-1,2,3,4-
tetrahydro-1,4-dimethylpyrazino[2,3-d]pyridazin-5(6H)-one (11)
(1.08 g, 82%) as a white solid: mp 159-161 °C; δH (400 MHz,
CDCl3) 2.84 (3H, t, 5JHF 1.7, N1(CH3)), 2.94 (2H, m, CH2), 3.00
(2H, m, CH2), 3.18 (3H, s, N4(CH3)), 11.01 (1H, br s, ring NH);
δC (100 MHz, CDCl3) 31.1 (N4(CH3)), 40.9 (s, C3), 43.1 (d, 4JCF
9.1, N1(CH3)), 47.5 (d, 4JCF 6.7, C2), 124.7 (d, 2JCF 27.2, C8a),
132.6 (d, 3JCF 9.7, C4a), 150.4 (d, 1JCF 230.4, C8), 159.1(s, C5);δF
(376 MHz, CDCl3) -97.6 (1F, s); m/z (EI+) 198 (100, [M+]), 183
(29, [M - Me]+), 169 (28), 168 (27, [M - 2Me]+), 42 (46). Anal.
Calcd for C8H11N4FO: C, 48.5; H, 5.6; N, 28.3. Found: C, 48.4;
H, 5.7; N, 28.6.
5,6,7,8-Tetrahydro-5,8-dimethyl-4-morpholinopyrazino[2,3-c]
pyridazin-3(2H)-one (12a). A 2-5 mL microwave vial was
charged with 5,6-difluoro-4-morpholinopyridazin-3(2H)-one
(0.25 g, 1.15 mmol) and N,N0-dimethylethylenediamine (0.25 mL,
2.30 mmol) and dissolved in dry acetonitrile (3 mL). The mixture
was irradiated at 150 °C for 20 min, after which time TLC
indicated complete conversion of starting material. Water
(5 mL) and dichloromethane (10 mL) were added and the layers
separated. The aqueous layer was washed with a further two
portions of dichloromethane (2ꢀ10 mL) before the combined
organic extracts were dried (MgSO4), filtered, and evaporated in
vacuo to yield a crude yellow material. This was recrystallized
from acetonitrile to yield 5,6,7,8-tetrahydro-5,8-dimethyl-4-mor-
pholinopyrazino[2,3-c]pyridazin-3(2H)-one (12a) (0.24 g, 79%)
as white crystals: mp >250 °C; νmax/cm-1 981, 1108, 1193, 1258,
1367, 1407, 1492, 1611, 2956 (br); δH (400MHz, CDCl3) 2.83 (3H,
s, CH3), 3.17 (2H, t, 3JHH 4.8, C(6/7)H2), 3.24 (4H, t, 3JHH 4.7,
C2’(H)), 3.30 (3H, s, CH3), 3.38 (2H, t, 3JHH 4.8, C(6/7)H2), 3.75
(4H, t, 3JHH 4.7, C30(H)), 9.14 (1H, br s, ring NH); δC (100 MHz,
CDCl3) 37.6 (s, CH3), 42.2 (s, CH3), 47.1 (s, C6/7), 49.5 (s, C2’),
51.6 (s, C6/7), 67.1 (s, C30), 124.1 (s, ArC), 137.9 (s, ArC), 144.3
(s, C8a), 161.3 (s, C3); m/z (ES+) 266 (100, [M + H]+). Anal.
Calcd for C12H19N5O2: C, 54.3; H, 7.2; N, 26.4. Found: C, 54.12;
H, 7.17; N, 26.30.
Reactions of Difluoropyridazinone with Amines. General
Procedure. 5,6-Difluoropyridazin-3(2H)-one derivative, amine,
and acetonitrile were placed in a 2-5 mL microwave vial which
was sealed and irradiated at 150 °C for the desired time. After
cooling, the solvent was evaporated and the residue dissolved in
dichloromethane (10 mL). Water (10 mL) was added and the
organic layer separated on a hydrophobic frit. The aqueous
layer was then extracted with further portions of dichloro-
methane (2ꢀ10 mL), and the combined organic extracts were
dried (MgSO4), filtered, and evaporated to yield the product
which could be further purified by recrystallization.
5-(N-Allyl-N-methylamino)-6-fluoro-4-morpholinopyridazin-
3(2H)-one (4b). 5,6-Difluoro-4-morpholinopyridazin-3(2H)-
one (200 mg, 0.921 mmol), N-allylmethylamine (0.18 mL,
1.84 mmol), and acetonitrile (3 mL) gave 5-(N-allyl-N-methyl-
amino)-6-fluoro-4-morpholinopyridazin-3(2H)-one (4b) (0.100 g,
43%) as white a solid: mp 86-87 °C; δH (400 MHz, CDCl3) 2.79
(3H, d, 4JHF 2.8, NMe), 3.45 (4H, t, 3JHH 4.6), 3.64 (2H, d, 4JHF
3
6.3, NCH2CHdCH2), 3.80 (4H, t, JHH 4.6), 5.18 (2H, m,
3
5
NCH2CHdCH2), 5.79 (1H, dquin, JHH 6.5, JHF 3.8,
NCH2CHdCH2), 11.27 (1H, br s, ring NH); δC (100 MHz,
4
4
CDCl3) 39.8 (d, JCF 4.8, NMe), 46.3 (s, C20), 57.4 (d, JCF 4.0,
NCH2CHdCH2), 67.5 (s, C30), 118.5 (s), 130.4, (d, 2JCF 28.0, C5),
133.9 (s), 140.7 (d, 3JCF 10.4, C4), 154.6 (d, 1JCF 236.5, C6), 161.6
(s, C3); δF (376 MHz, CDCl3) -94.5 (1F, s); m/z (ES+) 269 ([M+
H]+, 100); C12H17FN4O2 requires MH+ 269.1408, found MH+
269.1407.
Reactions of Difluoropyridazinone with Alkoxides. General
Procedure. The alcohol derivative was mixed with sodium
hydride (60% dispersion in mineral oil) and THF in a Radleys
Carousel tube under nitrogen with stirring. The 5,6-difluoro-
pyridazin-3(2H)-one derivative was added and the mixture
heated to reflux. After this period, the solvent was evaporated
and the residue dissolved in dichloromethane (10 mL). Water
(10 mL) was added and the organic layer separated on a
hydrophobic frit. The aqueous layer was then extracted
with further portions of dichloromethane (2ꢀ10 mL), and the
combined organic extracts were dried (MgSO4), filtered, and
evaporated followed by purification by mass-directed auto-
mated purification to yield the product(s).
5-(4-Bromophenoxy)-6-fluoro-4-morpholinopyridazin-3(2H)-
one (6b). 4-Bromophenol (0.398 g, 2.30 mmol), sodium hydride
(0.090 g, 2.30 mmol), 5,6-difluoro-4-morpholinopyridazin-3
(2H)-one (50 mg, 0.230 mmol) and THF (10 mL) gave 5-(4-
bromophenoxy)-6-fluoro-4-morpholinopyridazin-3(2H)-one (6b)
(0.0196 g, 23%) as a white solid: mp 173-174 °C; δH
3
3
(400 MHz, CDCl3) 3.55 (4H, t, JHH 4.8), 3.71 (4H, t, JHH
4.8), 6.82 (2H, d, 3JHH 9.1, Ar(C2H)), 7.47 (2H, d, 3JHH 9.1, Ar
(C3H)), 10.62 (1H, br s, ring NH); δC (100 MHz, CDCl3) 49.5
(s, C20), 67.2 (s, C30), 116.2 (s), 116.7 (s), 128.5 (d, 2JCF 30.4, C5),
130.1 (s), 140.0 (d, 3JCF 8.0, C4), 151.7 (d, 1JCF 235.7, C6), 155.7
(s), 160.6 (s, C3); δF (376 MHz, CDCl3) -101.1 (1F, s); m/z
(ES+) 372 (98, [81Br, M+H]+) 370 (100, [79Br, M+H]+);
C14H13BrFN3O3 requires [79Br, MH]+ 370.0197, found [79Br,
MH]+ 370.0192.
Acknowledgment. We thank EPSRC and GlaxoSmithK-
line R&D for a studentship (G.P.).
Supporting Information Available: Representative NMR
spectra of all new compounds and X-ray ORTEP diagrams,
structural details, and CIF files for 1, 2c,f, 3b, and 12a are
provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
5540 J. Org. Chem. Vol. 74, No. 15, 2009