Polysubstituted and ring-fused pyridazine systems from tetrafluoropyridazine

Article abstract of DOI:10.1016/j.tet.2016.12.006

Tetrafluoropyridazine 1 reacts with a range of oxygen-, nitrogen-, sulfur- and carbon-centred nucleophiles to give, in general, products 2 arising from substitution of fluorine para to ring nitrogen. Subsequent reaction of the trifluoropyridazine derivatives 2 gave a range of 4,5-di- and tri-substituted products 3 and 6. Related reactions of tetrafluoropyridazine 1 with difunctional nucleophiles gave [6,6]-, [5,6]- and [6,5,6]-polycyclic ring fused pyridazine scaffolds 4 and 9. Further functionalisation of scaffolds 4 by nucleophlic aromatic substitution processes involving displacement of fluorine atoms at activated sites ortho to ring nitrogen provide an indication of the synthetic possibilities offered using tetrafluoropyridazine as a starting material for the preparation of polysubstituted pyridazine and novel polyfunctional ring fused pyridazine systems with potential applications in the drug discovery arena.

Full text of DOI:10.1016/j.tet.2016.12.006

Accepted Manuscript
Polysubstituted and ring-fused pyridazine systems from tetrafluoropyridazine
Graham Pattison, Graham Sandford, Ian Wilson, Dmitrii S. Yufit, Judith A.K. Howard,
John A. Christopher, David D. Miller
PII:
S0040-4020(16)31274-1
10.1016/j.tet.2016.12.006
TET 28298
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 August 2016
Revised Date: 20 November 2016
Accepted Date: 6 December 2016
Please cite this article as: Pattison G, Sandford G, Wilson I, Yufit DS, Howard JAK, Christopher JA,
Miller DD, Polysubstituted and ring-fused pyridazine systems from tetrafluoropyridazine, Tetrahedron
(2017), doi: 10.1016/j.tet.2016.12.006.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Polysubstituted and ring-fused pyridazine systems from
tetrafluoropyridazine
Graham Pattison,a Graham Sandford,a* Ian Wilson,a Dmitrii S. Yufit,a Judith A.K. Howard,a John A.
Christopherb and David D. Millerb
a. Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, U.K.
b. GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts.,
U.K.
graham.sandford@durham.ac.uk
Abstract
Tetrafluoropyridazine 1 reacts with a range of oxygen-, nitrogen-, sulfur- and carbon-centred
nucleophiles to give, in general, products 2 arising from substitution of fluorine para to ring nitrogen.
Subsequent reaction of the trifluoropyridazine derivatives 2 gave a range of 4,5-di- and tri-substituted
products 3 and 6. Related reactions of tetrafluoropyridazine 1 with difunctional nucleophiles gave
[6,6]-, [5,6]- and [6,5,6]-polycyclic ring fused pyridazine scaffolds 4 and 9. Further functionalisation of
scaffolds 4 by nucleophlic aromatic substitution processes involving displacement of fluorine atoms at
activated sites ortho to ring nitrogen provide an indication of the synthetic possibilities offered using
tetrafluoropyridazine as a starting material for the preparation of polysubstituted pyridazine and novel
polyfunctional ring fused pyridazine systems with potential applications in the drug discovery arena.
Keywords: heterocyclic scaffold, perfluoroheterocycle, multi-functional pyridazine, nucleophilic
aromatic substitution.
1.
Introduction
1

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New efficient synthetic approaches to polyfunctional pyridazine derivatives and rare heterocyclic
systems derived from tetrafluoropyridazine are described in this paper.
While the first identification of a pyridazine ring within a natural product structure was reported
relatively recently,1 pyridazine heterocyclic sub-units have been incorporated into a number of
successful pharmaceutical products such as Sulfamethoxypyridazine and Nifurprazine (antibacterial
agents) and Minaprine (antidepressant) (Fig. 1).2 Consequently, new methodology that allows the rapid
synthesis of libraries of novel pyridazine derivatives bearing multiple functionality for incorporation in
drug discovery campaigns continues to be an important target for medicinal chemists.
Figure 1 Pharmaceuticals containing pyridazine sub-units
In general, pyridazine systems can be constructed by either a variety of ring-forming processes or
reactions of an appropriately functionalised pyridazine substrate.3 For example, construction of
pyridazine rings can be achieved by formation of the inter-heteroatom bond involving the
intramolecular oxidative coupling of two amino groups3a, reactions of 1,4-dicarbonyl compounds with
hydrazine3b-e and Diels-Alder type [4+2] cycloaddition (Carboni-Lindsey reaction) between 1,2,4,5-
tetrazine with either an alkene or alkyne substrate.3f,g Various approaches to the preparation of
polysubstituted pyridazines from appropriate pyridazine substrates have been reported, including
deprotonation of the parent heterocycle and subsequent trapping with an electrophile, such as reactions
with LiTMP3h or heteroaryl Grignard derivatives,3i palladium-catalyzed coupling of appropriate
halogenated pyridazine derivatives3j,k such as Negishi3l or Suzuki cross coupling processes,3m,n or
reaction of appropriate halogenated pyridazines by SNAr processes.3o-q Of course, all these approaches
have their advantages and disadvantages and the choice of synthetic strategy depends on the nature of
2

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the target pyridazine system, availability of appropriate substrates, regioselectivity of functionalisation,
functional group tolerance, cost, scalability and/or applicability to parallel synthesis techniques.
Additionally, a lack of structural diversity in pharmaceutical company compound collections is often
suggested to hamper the development of new drug lead candidates and, consequently, new heterocyclic
scaffolds with novel, patentable molecular architectures are of growing importance for further
exploration of chemical space in the search for new biologically active drug-like species.
Consequently, the synthesis of structurally novel polycyclic ring-fused pyridazine systems, for
example, would provide access to new areas of chemical space suitable for the assessment of novel
biological activities. New synthetic approaches to ring-fused pyridazine systems require efficient
access to polyheterocyclic cores which also bear suitable functional groups that would allow further
transformation to libraries of novel ring-fused heterocyclic derivatives.
Tetrafluoropyridazine 1 could be a highly versatile scaffold for the synthesis of a range of both
polysubstituted pyridazine systems and polyfunctional bi- and tri-cyclic fused ring systems because, in
principle, all four fluorine atoms could be replaced by reaction with a nucleophilic species through
sequential nucleophilic aromatic substitution processes.(Scheme 1) In this context, we demonstrated
that pentafluoropyridine can, for example, be transformed to a range of polysubstituted pyridine
derivatives by sequential reaction with a variety of mono- and bi-dentate nucleophilic species which
has allowed the synthesis of various polysubstituted bi- and tri-cyclic ring fused systems such as
pyridopyrazine4a-c and imidopyrazine4d derivatives bearing functionality for further structural
elaboration. Tetrafluoropyridazine 1 was first prepared some time ago5 but the chemistry of this
system has largely been limited to reactions in which methoxide and several amines have been reported
to provide products arising from substitution of fluorine at the 4-position5,6 whereas polysubstitution
processes, generally involving perfluoroalkylcarbanion nucleophiles,7 have rarely been reported.
Consequently, we chose to study reactions of tetrafluoropyridazine 1 with a range of mono- and di-
functional nucleophiles which could, potentially, lead to many novel multiply-substituted pyridazine
and ring-fused pyridazine systems that bear wide ranging functionality following a general synthetic
strategy outlined in Scheme 1.
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Nuc4
Nuc5
Nuc1
F
N
N
9
Nuc4 Nuc5
Nuc4
F
F
Nuc1
F
F
Nuc5
F
F
F
F
Nuc4 Nuc5
Nuc1
N
N
N
N
F
N
N
4
1
2
Nuc6
Nuc2
Nuc2
Nuc4
F
Nuc5
Nuc6
F
Nuc1
N
N
N
F
N
3
7
Nuc3
and/or
Nuc4
Nuc2
Nuc2
N
Nuc6
Nuc5
F
Nuc3
Nuc1
F
F
Nuc1
Nuc3
and/or
N
N
N
N
N
8
6
Scheme 1. General strategy for the synthesis of highly substituted and ring fused pyridazine derivatives
from tetrafluoropyridazine 1.
In this paper, we describe the synthesis of a range of polysubstituted, bi- and tri-cyclic ring fused
pyridazine systems from tetrafluoropyridazine 1 which allows access to some multiply-substituted
pyridazine derivatives and various very rare heterocyclic molecular frameworks by sequential SNAr
methodology suitable for parallel synthesis techniques.
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2.
Results and discussion
A series of reactions of tetrafluoropyridazine 1 with model monodentate oxygen-, nitrogen-, carbon-
and sulfur-centred nucleophiles were carried out to extend the range of systems available for further
functionalisation and are collated in Table 1. In general, reactions of nucleophiles with
o
tetrafluoropyridazine 1 occurred at 0 C or room temperature in the presence of the strong, non-
nucleophilic organic base di-isopropylethyl amine (DIPEA) and using THF as the reaction medium.
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Table 1. Reactions of tetrafluoropyridazine with monofunctional nucleophiles.
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In all cases, products 2a-k, obtained in high yields, were those derived from substitution of fluorine
located at the 4-position as we would expect from observations reported previously.5,6 This site is the
most activated position towards nucleophilic attack as it is para to the activating ring nitrogen and has
two ortho and one meta activating fluorine atoms, following principles for processes involving highly
reactive heterocycles.5,8 The structures of the products 2a-k followed from 19F NMR analysis in which
_
_
_
_
three resonances at ca. 80, 90 and 135 ppm were observed, where resonances occurring at ca. 90
ppm are indicative of fluorine located at sites ortho to ring nitrogen as is the case here.9
Whilst all nitrogen- and oxygen-centred nucleophiles gave high yields of mono-substituted products, in
contrast, reaction of one equivalent of thiophenol and tetrafluoropyridazine 1 gave only the 4,5-
disubstituted product 2l with no monosubstituted product observed by 19F NMR analysis of the reaction
mixture. This reflects the strong ortho activating effect of the sulfur atom which makes the
monosubstituted product more reactive towards nucleophiles than 1 itself.10 Thus, a higher yield of 2l
could be obtained upon reaction of 1 with two equivalents of thiophenol in similar reaction conditions.
In contrast, ethanethiol gave only mono-substituted product 2k consistent with the decreasing electron
withdrawing ability of the ethanethio substituent compared to the phenylthio case.
Reaction of 1 with phenylmagnesium bromide gave a mixture of two monosubstituted products 2m and
2n in a 5:1 ratio by 19F NMR analysis of the crude reaction mixture, arising from substitution of the 4-
and 3-positions respectively, from which the major product 2m could be purified by repeated
recrystallisation. In this reaction, some competing substitution occurs at the 3-position due to the
increased reactivity of the nucleophile which allows substitution at the less activated site ortho to ring
nitrogen. In the case of reaction of 1 with methylmagnesium bromide, decomposition occurs, likely due
to the highly basic reaction mixture that causes deprotonation of the pyridazyllic protons present in any
product formed leading to complex reaction mixtures as observed in similar reactions of highly
fluorinated pyridine derivatives.11
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Scheme 2. Reaction of 1 with phenyl magnesium bromide
Trifluoropyridazine derivatives 2 are, of course, still very electrophilic in nature and, in principle,
products arising from substitution of the remaining ring fluorine atoms or the substituent itself are
possible upon reaction with subsequent nucleophilic species. Consequently, our next series of reactions
was aimed at exploring the behaviour of four selected representative trifluoropyridazine derivatives
2a,h,k,m with model nitrogen-, oxygen-, sulfur- and carbon-centred nucleophiles to determine how the
4-substituent affects further nucleophilic substitution processes (Table 2). All reactions were performed
using similar conditions to those described above.
8

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Table 2. Reactions of trifluoropyridazines 2a,h,k,m with nucleophiles
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Reactions of model nucleophiles with trifluoropyridazine derivatives 2a,h,k,m gave products 3a-h
arising from substitution at the 5-position, para to ring nitrogen. 4,5-Disubstitution was confirmed by
_
19F NMR analysis which showed only resonances occuring at ca. 85 ppm for each compound 3a-h,
consistent with the presence of fluorine ortho- to ring nitrogen. Reactions were noticeably slower for
the trifluorinated pyridazines 2a,k,l,m than 1 as would be expected.
Having established that 1 reacts, in the majority of cases, regioselectively with two equivalents of
nucleophile successively to give products 3a-h exclusively from sequential substitution of the 4- and 5-
positions, we carried out a series of experiments to prepare ring-fused systems 4 arising from
corresponding SNAr reactions of 1 with difunctional nucleophiles. Initial nucleophilic attack on 1 at the
4-positon, followed by subsequent intramolecular cyclisation by substitution of fluorine attached to the
most activated 5-position would be expected to occur. Consequently, reactions of tetrafluoropyridazine
1 with a small range of representative difunctional nitrogen nucleophiles were performed (Table 3). In
all cases, the bi- or tri-cyclic ring fused systems 4a-g derived from reaction at the most activated 4- and
5-positions were synthesized and isolated in good yield. Symmetrical ring-fused products 4a,b,f were
readily identified by the observation of only one resonance in the 19F NMR spectra and similar
equivalencies in the 1H and 13C NMR spectra. Non-symmetric bicyclic and tricyclic products 4c,d,e,g
displayed two distinct 19F NMR resonances at ca. -92.6 and -94.6 ppm which are, again, both
characteristic of fluorine located ortho to ring nitrogen. Interestingly, these results show opposite
regioselectivity to a cyclisation reaction previously performed between tetrafluoropyridazine and
catechol, which cyclized between C4 and C3.12
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Table 3. Synthesis of polycyclic systems 4 from 1
F
F
F
Conditions
+
F
Dinucleophile
Product 4
N
N
1
Nucleophile
Product, Yield %
N
Nucleophile
Product, Yield %
Conditions
Conditions
Me
N
H
NaHCO3
MeCN
rt, 4 h
MeCN
F
N
F
N
N
F
Me
MW, 150 oC, 10 min
N
H
N
NH2
N
N
N
N
F
4a, 92%
4d, 58%
Br
Ph
N
1) NaHCO3,
MeCN
Br
NH
NH2
HN
MeCN
MW, 150 oC, 10 min
F
reflux, 3 d;
2) DIPEA, MeCN,
MW, 180 oC, 15
min
N
N
NH2
N
F
N
N
F
N
4b, 46%
N
F
4e, 40%
S
N
NaHCO3
MeCN
rt, 2 h
F
S
HS
N
NaHCO3
MeCN
reflux, 16 h
F
SH
N
N
NH2
N
N
F
N
F
4f, 65%
4c, 82%
S
N
F
F
NaHCO3
MeCN
reflux, 16 h
H2N
S
N
N
4g, 62%
Reaction of 1 with benzamidine in acetonitrile at reflux temperature in the presence of four equivalents
of sodium bicarbonate yielded the uncyclised amidine derivative 5. A range of bases were reacted with
5 in an attempt to effect the desired cyclisation but n-BuLi, LDA and LiHMDS gave complex product
mixtures. However, cyclisation could be achieved using DIPEA and 4b was obtained in good yield
after microwave irradiation at 180 oC for 15 minutes in an overall two step process. Annelation of 1 by
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cyclic amino-imine and 2-aminopyridine derivatives led to the corresponding tricyclic systems 4c-e
respectively in high yields.
Whilst imidazo[4,5-d]pyridazines13 and thiazolo[4,5-d]pyridazines14 are relatively common, formed by
reaction of appropriate 4,5-diaminopyridazines with acid chloride derivatives13 and thiazole 4,5-
dicarboxaldehyde with hydrazine respectively14, many other polycyclic systems incorporating a
pyridazine ring subunit are very rarely reported in either the academic or patent literature and
polyfunctional systems suitable as substrates for analogue synthesis have not been described. Only a
very few examples of related pyridazino-tetrahydropyridazine,15 dithiino-pyridazine,16 pyridazino-
thiazine and dioxino- pyridazine17 derivatives and tricyclic systems18 have been synthesised from
reaction of appropriate chlorinated pyridazines and dinucleophiles or by reaction of appropriate
dinitriles with hydrazine.
Sequential trisubstitution of 1 is also possible when a sufficiently activated difluoropyridazine 3f was
further reacted with an appropriate nucleophile. Disubstituted system 3f, was reacted with morpholine
upon microwave irradiation at 150 °C for 90 min (Scheme 3) and 19F NMR spectroscopy of the product
mixture showed only a single product 6 which could be isolated in 71% yield by column
chromatography and its structure was confirmed by X-ray crystallography (Figure 2). The thiophenoxy
group is ortho- activating to some extent and the morpholino group is slightly deactivating, explaining
the high regioselectivity of this process.
Scheme 3. Synthesis of trisubstituted derivative 6
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Figure 2. Molecular structure of trisubstituted derivative 6
Similarly, all the [5,6]- and [6,6]-ring fused scaffolds synthesised by the processes outlined in Table 3
possess fluorine atoms attached to the pyridine ring which, in principle, are also susceptible towards
nucleophilic displacement. Consequently, we studied reactions of representative polycyclic products
4b-d with a small range of model nucleophiles to illustrate the potential of these novel scaffolds for the
synthesis of polycyclic multi-functionalised derivatives (Scheme 4).
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Scheme 4. Reactions of ring fused systems 4b-d with nucleophiles
Ph
Ph
HN
HN
H
N
F
F
N
N
MeCN
Bu
+ n-BuNH2
N
MW, 150 oC, 20 min
N
Bu
2 equiv.
N
N
N
H
4b
7a, 35%
N
N
O
N
F
MeCN
F
N
N
F
+
MW, 150 oC, 20 min
N
N
H
N
N
N
4c
O
7b, 72%
Nuc (2.5 eq)
MeCN
MW, 150 oC, 10 min
N
N
N
+
N
F
N
Nuc
N
F
F
F
N
N
N
N
N
Nuc
N
8
7
4d
Nuc
NaOMe
EtNH2
Et2NH
7c, Nuc = OMe, 40% 7c : 8c, 76 : 24
7d, Nuc = NHEt, 65% 7d : 8d, 79 : 21
7e, Nuc = NEt2, 70% 7e : 8e, 95 : 5
Reaction of [6,6]-fused system 4a with nucleophiles was not successful even after prolonged heating
with various reactive nucleophiles, reflecting the deactivating influence of the two amino substituents
attached to the pyridazine ring. However, reaction of imidazopyridazine 4b with n-butylamine yielded
the disubstituted system 7a, arising from replacement of both remaining ring fluorine atoms while
reaction of tricyclic scaffold 4c with morpholine gave 7b regioselectively (Scheme 3) and the structure
was confirmed by X-ray crystallography (Fig. 3).
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Figure 3. Molecular structure of 7b
The regioselectivity of the reaction between 4c and morpholine can be explained by a consideration of
the relative stabilities of the Meisenheimer intermediates formed by reaction at either the C-1 or C-4
sites. Attack at C-1 allows delocalisation of the negative charge formed over the pyridazine and
imidazopyridazine ring system giving a more stable intermediate whilst attack at C-4 only allows
delocalisation over the pyridazine ring (Scheme 5).
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Scheme 5. Regioselectivity of nucleophilic substitution for reaction of 4c
Tricyclic system 4d reacted with nucleophiles under microwave irradiation in acetonitrile (Scheme 4)
to give major products arising from substitution of fluorine at C-1. While small quantities of products
arising from substitution of C-4 of the pyridazine ring were observed by 19F NMR analysis of the
reaction mixture, major products 7c,d could be isolated by column chromatography or recrystallisation
of the crude product mixture. X-ray crystallography confirmed the structure of the 1-diethylamino
derivative 7e (Fig. 4) and NMR data obtained for 7a,b were comparable to those obtained for 7e. In
this case, nucleophilic attack at C-1 leads to stabilisation of the Meisenheimer intermediate over the
entire aromatic system whilst attack at C-4 only allows charge to be delocalised over the pyridazine
ring and, consequently, reactions arising from displacement of fluorine at C-1 are preferred.
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Figure 4. Molecular structure of 7e
An alternative method for the synthesis of functionalized pyridazine ring fused polycyclic derivatives is
to carry out annelation reactions of monofunctionalised trifluoropyridazines 2 with appropriate
difunctional nucleophiles (Table 4).
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Table 4. Reaction of trifluoropyridazines 2a,k with difunctional nucleophiles
R
R
Difunctional
nucleophile
Nuc1
Nuc2
F
F
F
F
N
N
Conditions
N
N
2
9
2
Product, Yield %
2
Product, Yield %
O
Conditions
Conditions
O
H
NH2
OH
S
H
S
N
N
N
N
N
F
F
F
F
H
N
N
F
F
F
F
N
DIPEA, THF
rt, 5 d
N
N
O
N
N
DIPEA, THF
100 oC, microwave,
5 min
N
N
N
9e, 75%
2a
2k
9a, 84%
O
N
O
NH2
SH
S
S
SH
OH
H
N
F
F
F
F
N
F
F
N
S
F
N
N
DIPEA, THF
100 oC, microwave
30 min
S
N
N
DIPEA, THF
rt, 16 h
F
N
2k
N
9f, 63%
O
N
2a
9b, 68%
S
S
F
F
F
H2N
N
F
N
H
S
S
N
N
DIPEA, THF
N
H
N
N
N
F
F
F
F
N
N
o
150 C, microwave
2k
N
30 min
DIPEA, THF
rt, 16 h
N
9g, 14%
N
N
N
2k
S
9c, 77%
S
F
F
F
F
N
SH
OH
H2N
N
S
N
N
S
N
F
F
N
N
DIPEA, THF
rt, 7 d
S
F
2k
N
9h, 50%
F
N
DIPEA, THF
rt, 16 h
N
O
N
S
O
O
2k
O
S
9d, 74%
F
F
F
EtO
OEt
DIPEA, THF
180 oC, microwave
F
N
N
N
O
N
2k
90 min
9i, 28%
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Indeed, reaction of N,N’-dimethylethylene diamine with 2a gave the desired fused product 9a in good
yield after stirring in THF at room temperature and, similarly, reaction with 2-mercaptophenol gave
tricyclic product 9b. 4-(Ethylthio)-3,5,6-trifluoropyridazine 2k was also used for the synthesis of ring
fused systems and reaction with N,N’-dimethylethylene diamine rapidly gave fused bicyclic product 9c
in good yield. 2-Mercaptophenol gave the fused bicyclic product 9d as the only product as observed by
19F NMR analysis of the crude reaction mixture and crystals that were suitable for analysis by X-ray
crystallography allowed the confirmation of the structure (Fig. 5). It appears that the initial attack is
performed by the sulfur atom giving initial substitution para to ring nitrogen, further activating the
intermediate to nucleophilic attack by the oxygen atom at the adjacent site.
Figure 5. Molecular structures of 9d, 9e and 9h.
Reaction of 2k with 2-aminophenol using microwave irradiation at 100 °C for five minutes gave the
tricyclic product 9e, confirmed by X-ray crystallography (Fig. 5), which demonstrated that the product
was formed via initial attack by nitrogen followed by cyclisation through oxygen. Similarly, 2-
aminobenzenethiol, 2-aminopyridine, 2-amino-3-picoline and ethyl acetoacetate gave the desired
polycyclic products 9f-i respectively after reaction with 4-(ethylthio)-3,5,6-trifluoropyridazine 2k
under microwave irradiation.
3.
Conclusions
Tetrafluoropyridazine 1 may be used as a very effective scaffold for the synthesis of a range of 4,5-
disubstituted pyridazine systems bearing oxygen, nitrogen, sulfur and carbon functionality. Further
substitution of the difluorinated systems gave mixtures of trisubstituted pyridazine systems, processes
19

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which were particularly regioselective in the presence of an ortho-activating sulfur substituent.
Consequently, we have further extended our general strategy for using perfluorinated heteroaromatic
scaffolds for analogue synthesis to pyridazine systems.
Novel bi- and tri-cyclic heterocyclic systems have been synthesised by reaction of tetrafluoropyridazine
with bifunctional nitrogen centred nucleophiles providing access to tetrahydropyrazino-pyridazine,
imidazopyridazine and tetraazafluorene scaffolds. The presence of fluorine atoms attached to sites
activated towards nucleophilic attack allows functionalisation of these scaffolds and representative
examples of nucleophilic aromatic substitution processes have been established. The developing use of
highly fluorinated heteroaromatic derivatives as starting materials for heterocyclic synthesis has been
further expanded to ring fused pyridazine systems.
The general strategy outlined in Scheme 1 has allowed the synthesis of a wide range of
polyfunctionalised and ring-fused pyridazine derivatives from tetrafluoropyridazine and the synthetic
methodology is summarised in Scheme 6, demonstrating the diverse molecular structures that can be
accessed very readily after a few simple operations.
Scheme 6. Synthesis of pyridazine based systems from tetrafluoropyridazine
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4.
Experimental
General
Reactions were performed under an atmosphere of argon gas using dry solvents. Microwave reactions
were performed on a Biotage Initiator 60 EXP. Reactions were monitored by 19F NMR or TLC on
silica gel TLC plates. Column chromatography was carried out on silica gel (Merck no. 109385,
particle size 0.040 – 0.063nm) or using a Biotage Horizon or Isco Companion flash chromatography
system. Mass directed HPLC was performed on a Supelco LCABZ++ column using MicroMass
MassLynx v4.0 software. Melting points were recorded using a Gallenkamp melting point apparatus at
atmospheric pressure and are uncorrected. NMR spectra were recorded in deuteriochloroform, unless
otherwise stated, using trichlorofluoromethane as an internal reference on a Varian Mercury 400 or
Bruker Avance 400 operating at 400MHz (1H NMR), 376MHz (19F NMR) and 100MHz (13C NMR), or
a Varian Inova 500 operating at 500MHz (1H NMR), 470MHz (19F NMR) and 125MHz (13C NMR), or
a Varian VNMRS-700 operating at 700MHz (1H NMR), 658MHz (19F NMR) and 175MHz (13C
NMR). Chemical shifts are given in ppm and coupling constants are recorded in Hertz. Mass spectra
were recorded on a Thermoquest Trace GC-MS spectrometer (in electron ionisation mode) or a
Micromass LCT LC-MS spectrometer (in electrospray ES+ mode). Exact mass measurements were
performed on a Thermo-Finnigan LTQ-FT spectrometer. Gas chromatography was carried out on a
Thermo TRACE GC. Analytical HPLC was performed on an Analytical Varian LC (5ml/min).
Elemental analyses were obtained using an Exeter Analytical E-440 Elemental Analyser.
X-ray crystallography
The X-ray single crystal data have been collected on a Bruker SMART CCD 1K (compounds 7b and
9e), a Bruker SMART CCD 6000 (compounds 7e, 9d and 9h) and a Rigaku R-AXIS SPIDER IP
(compound 6) diffractometers (graphite monochromators, λMoKα, λ =0.71073Å) equipped with a
Cryostream (Oxford Cryosystems) open-flow nitrogen cryostats at the temperatures 120(2) K. All
structures were solved by direct method and refined by full-matrix least squares on F2 for all data using
Olex219 and SHELXTL20 software. All non-disordered non-hydrogen atoms were refined
21

ACCEPTED MANUSCRIPT
anisotropically, hydrogen atoms were refined isotropically, the hydrogen atoms in the twinned structure
9e were placed in the calculated positions and refined in riding mode. Crystallographic data for the
structures have been deposited with the Cambridge Crystallographic Data Centre as supplementary
publications CCDC-1486844-1486849.
Reactions of Tetrafluoropyridazine 1 with nucleophiles
General procedure
A mixture of tetrafluoropyridazine 1, DIPEA, amine and THF (10 mL) was stirred for the required time
under an atmosphere of nitrogen. The mixture was evaporated to dryness in vacuo, partitioned between
ethyl acetate (20 mL) and water (20 mL), the phases were separated and the aqueous phase was
extracted further by ethyl acetate (3 x 20 mL). The combined organic phases were dried (MgSO4) and
evaporated in vacuo. Purification by column chromatography or HPLC on silica gel using cyclohexane
and ethyl acetate as eluent gave the pure product.
4-(3,5,6-Trifluoro-pyridazin-4-yl)morpholine 2a
Tetrafluoropyridazine 1 (781 mg, 5.14 mmol), DIPEA (1.35 mL, 7.73 mmol), morpholine (0.45 mL,
5.17 mmol) and THF (10 mL) after stirring at 0 °C for 2 h gave 4-(3,5,6-trifluoro-4-
pyridazinyl)morpholine 2a (908 mg, 81%) as white crystals; mp 34.5 – 36.1 °C (Found: [MH]+,
220.06923. C8H8F3N3O requires: [MH]+, 220.06922); νmax(film)/cm-1 2970, 2902, 2860 and 1595; δH
3.54 (4 H, br s, CH2N), 3.80 - 3.86 (4 H, m, CH2O); δC 50.1 (t, 4JCF 4.4, CH2N), 66.7 (s, CH2O), 129.3
1
3
(ddd, 2JCF 24.8, 2JCF 24.8, 3JCF 3.2, C-4), 139.7 (ddd, JCF 270.8, 2JCF 28.8, JCF 9.6, C-5), 156.8 (ddm,
3
1
2
1JCF 240.5, JCF 12.0, C-6), 158.0 (dd, JCF 240.5, JCF 3.2, C-3); δF -143.8 – -143.4 (1F, m, F-5) -98.6
3
4
3
5
(1 F, dd, JFF 31.0, JFF 24.1, F-3) -80.8 (1 F, dd, JFF 28.7, JFF 28.7, F-6); m/z (ES+) 220 ([MH]+,
100%).
N,N-Diethyl-3,5,6-trifluoro-4-pyridazinamine 2b
Tetrafluoropyridazine 1 (774 mg, 5.09 mmol), DIPEA (1.33 mL, 7.64 mmol), diethylamine (0.53 mL,
5.09 mmol) and THF (10 mL) after stirring at 0 °C for 19 h gave N,N-diethyl-3,5,6-trifluoro-4-
pyridazinamine 2b (852 mg, 82%) as a yellow oil; (Found: [MH]+, 206.08973. C8H8F3N3O requires:
3
3
206.08996); νmax(film)/cm-1 2983, 2940 and 1587; δH 1.28 (6 H, t, JHH 7.1, CH3), 3.47 (4 H, qt, JHH
22

ACCEPTED MANUSCRIPT
5
3
7.1, JHF 1.5, CH2); δC 13.9 (s, CH3), 46.8 (t, 4JCF 5.2, CH2), 129.2 (dt, 2JCF 25.6, JCF 4.8, C-4), 137.9
(ddd, 1JCF 266.8, 2JCF 28.8, 3JCF 11.2, C-5), 157.0 (dd, 1JCF 238.1, 3JCF 2.4, C-3), 157.1 (dd, 1JCF 238.9,
2JCF 4.0, C-6); δF -146.8 (1 F, dd, 3JFF 27.5, 4JFF 25.2, F-5), -100.7 (1 F, dd, 4JFF 28.7, 5JFF 24.1, F-3), -
81.4 (1 F, dd, 3JFF 28.7, 5JFF 28.7 F-6); m/z (ES+) 206 ([MH]+, 100%).
N-Allyl-3,5,6-trifluoro-N-methylpyridazin-4-amine 2c
Tetrafluoropyridazine 1 (785 mg, 5.16 mmol), DIPEA (1.35 mL, 7.73 mmol), N-methylallylamine
(0.50 mL, 5.16 mmol) and THF (10 mL) after stirring at 0 °C for 3.5 h gave N-allyl-3,5,6-trifluoro-N-
methylpyridazin-4-amine 2c (861 mg, 82%) as a pale yellow oil; (Found: [M]+, 204.07433. C8H8F3N3O
requires: [M]+, 204.07431); νmax(film)/cm-1 2908, 1644 and 1593; δH 3.14 (3 H, t, 5JHF 3.2, CH3), 3.97
3
3
2
3
2
(2 H, d, JHH 5.9, CH2), 5.29 (1 H, dd, JHH 16.9, JHH 1.2, HCH), 5.32 (1 H, dd, JHH 10.3, JHH 1.2,
4
4
HCH), 5.82 - 5.94 (1 H, m, CH); δC 39.6 (t, JCF 5.6, CH3), 57.3 (t, JCF 4.8, CH2), 119.1 (s, =CH2),
2
3
1
2
3
130.1 (dt, JCF 25. 6, JCF 4.8, C-4), 132.2 (s, CH), 138.4 (ddd, JCF 267.6, JCF 28.0, JCF 9.6, C-5),
1
3
1
2
3
157.0 (dd, JCF 239.7, JCF 12.8, C-3), 157.2 (dd, JCF 238.9, JCF 4.8, C-6); δF -145.6 (1 F, dd, JFF
3
27.5, 4JFF 27.5, F-5) -100.0 (1 F, dd, 4JFF 28.7, 5JFF 25.2, F-3) -80.9 (1 F, dd, JFF 28.7, 5JFF 28.7, F-6);
m/z (ES+) 204 ([M]+, 100%).
N-[(4-bromophenyl)methyl]-3,5,6-trifluoro-N-methyl-4-pyridazinamine 2d
Tetrafluoropyridazine 1 (786 mg, 5.17 mmol), DIPEA (1.3 mL, 7.46 mmol), 1-(4-bromophenyl)-N-
methylmethanamine (1.05 mL, 5.26 mmol) and THF (10 mL) after stirring at rt for 3 h gave N-[(4-
bromophenyl)methyl]-3,5,6-trifluoro-N-methyl-4-pyridazinamine 2d (1.122 g, 65%) as white crystals,
mp 77.1 – 78.5 °C (Found: C, 43.4; H, 2.70; N, 12.4. C12H9BrF3N3 requires: C, 43.4; H, 2.7; N,
5
5
12.6%); νmax(film)/cm-1 2940, 1601, 1573 and 1560; δH 3.09 (3 H, dd, JHF 3.8, JHF 2.7, CH3) 4.53 (2
H, s, CH2) 7.15 (2 H, d, 3JHH 8.5, H2C-C-CH) 7.49 (2 H, d, 3JHH 8.5 Hz, Br-C-CH); δC 40.0 (t, 4JCF 5.2,
2
CH3), 57.6 (t, 4JCF 4.8, CH2), 121.9 (br s, C-Br), 129.0 (s, H2C-C-CH), 130.2 (ddd, JCF 24.8, 2JCF 4.8,
3JCF 3.2, C-4), 132.0 (s, Br-C-CH), 134.9 (br s, H2C-C), 139.0 (ddd, 1JCF 270.8, 2JCF 29.6, 3JCF 10.4, C-
1
3
1
2
3
5), 156.9 (dd, JCF 240.5, JCF 11.9, C-6), 157.4 (dd, JCF 239.7, JCF 3.9, C-3); δF -144.3 (1 F, t, JFF
4
5
3
26.4, F-5) -99.4 (1 F, dd, JFF 27.5, JFF 25.2, F-3) -80.6 (1 F, dd, JFF 29.8, 5JFF 29.8, F-6); m/z (ES+)
334.1 ([MH]+, 100%).
Methyl N-methyl-N-(3,5,6-trifluoro-4-pyridazinyl)glycinate 2e
23

ACCEPTED MANUSCRIPT
Tetrafluoropyridazine 1 (801 mg, 5.27 mmol), DIPEA (2.29 mL, 13.17 mmol), sarcosine methyl ester
hydrochloride (735 mg, 5.27 mmol) and THF (10 mL), after stirring at rt for 3 d gave methyl N-methyl-
N-(3,5,6-trifluoro-4-pyridazinyl)glycinate 2e (616 mg, 50%) as a pale yellow oil; (Found: C, 40.5; H,
3.3; N, 17.7. C8H8F3N3O requires: C, 40.9; H, 3.4; N, 17.9%); νmax(film)/cm-1 2958, 1747 and 1597; δH
5
5
4
3.27 (3 H, dd, JHF 3.4, JHF 2.7, NCH3), 3.81 (3 H, s, OCH3), 4.14 (2 H, s, CH2); δC 42.1 (t, JCF 5.6,
NCH3), 52.5 (s, OCH3), 55.3 (dd, 4JCF 6.4, 4JCF 4.8, CH2), 129.62 (ddd, 2JCF 25.6, 2JCF 4.8, 3JCF 3.2, C-
2
1
4), 138.77 (ddd, 1JCF 269.2, JCF 28.8, 3JCF 9.6, C-5), 156.9 (d, 1JCF 240.0, C-3), 157.0 (dd, JCF 238.9,
2JCF 3. 9, C-6), 169.3 (s, C=O); δF -144.6 (1 F, t, 3JFF 26.4, F-5), -99.3 (1 F, dd, 4JFF 28.7, 5JFF 24.09, F-
3), -81.0 (1 F, t, 3JFF 28.7, F-6); m/z (ES+) 236.1 ([MH]+, 100%).
3,5,6-Trifluoro-N-phenylpyridazin-4-amine 2f
Tetrafluoropyridazine 1 (776 mg, 5.10 mmol), DIPEA (1.35 mL, 7.73 mmol) and aniline (0.46 mL,
5.10 mmol) in THF (10 mL), after stirring at 0 °C for 4 h and purification by column chromatography
on silica gel using ethyl acetate:hexane as eluent, gave 3,5,6-trifluoro-N-phenylpyridazin-4-amine 2f
(895 mg, 78%) as a white solid, mp 123.2 – 124.0 °C (Found: C, 53.6; H, 2.8; N, 18.7. C10H6F3N3
requires: C, 53.3; H, 2.7; N, 18.7%); δH 6.47 (1 H, br. s, NH), 7.15 – 7.40 (5 H, m, ArH); δC 122.7 (d,
1
5JCF 2.6, C-2’), 124.2 – 124.3 (m, C-4), 126.5 (s, C-4’), 129.4 (s, C-3’), 136.5 (ddd, JCF 272.3, 2JCF
29.9, 3JCF 6.9, C-5), 137.1 (s, C-1’), 156.8 (dd, 1JCF 238.2, 2JCF 3.3, C-6), 156.9 (d, 1JCF 237.7, C-3); δF
4
5
5
-141.5 (1 F, dd, JFF 25.4, 3JFF 24.5, F-5), -98.9 (1 F, dd, JFF 29.5, 3JFF 24.5, F-6), -89.0 (1 F, dd, JFF
29.5, 3JFF 25.4, F-3); m/z (ES+) 224.9 ([MH]+, 100%).
3,4,6-Trifluoro-5-(2-propen-1-yloxy)pyridazine 2g
Tetrafluoropyridazine (780 mg, 5.13 mmol), DIPEA (1.3 mL, 7.46 mmol), allyl alcohol (0.36 mL, 5.26
mmol) and THF (10 mL) after stirring at reflux for 24 h gave 3,4,6-trifluoro-5-(2-propen-1-
yloxy)pyridazine 2g (716 mg, 73%) as a colourless oil; (Found: [MH]+, 191.04277. C7H5F3N2O
3
requires: [MH]+, 191.04267); νmax/cm-1 2898, 1648 and 1611; δH 5.03 (2 H, dd, JHH 6.0, 5JHF 0.9, O-
CH2), 5.44 (1 H, dd, 3JHH 10.5, 2JHH 1.0, CHH), 5.51 (1 H, dd, 3JHH 16.9, 2JHH 0.97, CHH), 5.96 - 6.09
3
(1H, m, CH); δC 74.6 (dd, 4JCF 5.6, JCF 1.6, O-CH2), 121.4 (s, CH2), 130.5 (s, CH), 136.0 - 136.4 (m,
1
C-5), 140.1 (ddd, 1JCF 277.2, 2JCF 28.8, 3JCF 7.9, C-4), 156.7 (ddd, JCF 242.0, 3JCF 11.2, 4JCF 1.6, C-6),
1
3
4
5
158.7 (d, JCF 242.9, C-3); δF -146.6 (1 F, dd, JFF 25.2, 5JFF 25.2, F-4), -95.8 (1 F, dd, JFF 29.8, JFF
26.4, F-6), -87.6 (1 F, dd, 3JFF 27.5, 5JFF 27.5, F-3); m/z (ES+) 191.0 ([MH]+, 100%).
24

ACCEPTED MANUSCRIPT
3,4,6-Trifluoro-5-[(1-methylethyl)oxy]pyridazine 2h
Tetrafluoropyridazine 1 (780 mg, 5.13 mmol), DIPEA (1.3 mL, 7.46 mmol), isopropanol (0.41 mL,
5.26 mmol) and THF (10 mL) after stirring at reflux for 24 h gave 3,4,6-trifluoro-5-[(1-
methylethyl)oxy]pyridazine 2h (713 mg, 72%) as a colourless oil; (Found: [MH]+, 193.05830.
3
C7H7F3N2O requires: [MH]+, 193.05832); νmax/cm-1 2990, 2941 and 1608; δH 1.47 (6 H, dd, JHH 6.1,
6JHF 0.8, CH3), 5.02 - 5.14 (1 H, m, CH); δC 22.5 (s, CH3), 78.8 (d, 4JCF 4.0, CH), 136.0 - 136.2 (m, C-
1
2
3
1
4
5), 140.0 (ddd, JCF 275.8, JCF 28.6, JCF 7.8, C-4), 156.7 (ddd, JCF 239.7, 3JCF 11.2, JCF 1.6, C-6),
159.1 (ddd, 1JCF 246.1, 2JCF 8.8, 4JCF 2.4, C-3); δF -147.0 (1 F, dd, 3JFF 25.2, 4JFF 25.2, F-4) -96.1 (1 F,
dd, 4JFF 28.7, 5JFF 26.4, F-6) -87.9 (1 F, dd, 3JFF 28.7, 5JFF 28.7, F-3); m/z (ES+) 193.2 ([MH]+, 100%).
4-(Cyclohexyloxy)-3,5,6-trifluoropyridazine 2i
Tetrafluoropyridazine 1 (777 mg, 5.11 mmol), DIPEA (1.3 mL, 7.46 mmol), cyclohexanol (0.55 mL,
5.29 mmol) and THF (10 mL) after stirring at rt for 6 d gave 4-(cyclohexyloxy)-3,5,6-
trifluoropyridazine 2i (752 mg, 63%) as a colourless oil; (Found: C, 51.7; H, 4.5; N, 11.8.
C10H11F3N2O requires: C, 51.7; H, 4.8, N, 12.1%); νmax(film)/cm-1 2940, 2863 and 1607; δH 1.02 - 2.37
(10 H, m, CH2), 4.80 (1 H, br s, CH); δC 23.0 (s, C-3’), 24.9 (s, C-4’), 32.0 (s, C-2’), 83.3 (d, 4JCF 3.4,
1
4
C-1’), 135.8 - 136.0 (m, C-4), 140.2 (ddd, JCF 275.6, 2JCF 27.9, JCF 7.9, C-5), 156.7 (ddd, 1JCF 242.0,
3JCF 11.1, 4JCF 1.6, C-3), 159.3 (dd, 1JCF 244.4, 2JCF 2.4, C-6); δF -146.3 (1 F, dd, 3JFF 26.4, 4JFF 26.4, F-
4
5
3
5), -95.8 (1 F, dd, JFF 29.8, JFF 26.4, F-3), -87.5 (1 F, dd, JFF 28.7, 5JFF 28.7, F-6); m/z (ES+) 233.2
([MH]+, 100%).
3,4,6-Trifluoro-5-[(4-methylphenyl)oxy]pyridazine 2j
Tetrafluoropyridazine 1 (768 mg, 5.05 mmol), DIPEA (1.3 mL, 7.46 mmol), p-cresol (0.53 mL, 5.07
mmol) and THF (10 mL) after stirring at rt for 26
h
gave 3,4,6-trifluoro-5-[(4-
methylphenyl)oxy]pyridazine 2j (740 mg, 60%) as a colourless oil (Found: C, 54.9; H, 2.9; N, 11.4.
C11H7F3N2O requires: C, 55.0; H, 2.9; N, 11.7%); νmax(film)/cm-1 2928, 1614, 1606 and 1571; δH 2.38
3
4
(3 H, s, CH3), 6.97 (2 H, d, JHH 8.7, O-C-CH), 7.21 (2 H, dd, 3JHH 8.7, JHH 0.7, H3C-C-CH); δC 20.7
(s, CH3), 116.9 (s, O-C-CH), 130.5 (s, H3C-C-CH), 134.5 - 134.7 (m, C-5), 135.7 (s, H3C-C), 141.8
(ddd, 1JCF 282.8, 2JCF 27.9, 3JCF 7.1, C-4), 153.0 (s, O-C), 156.7 (ddd, 1JCF 243.6, 2JCF 9.9, 4JCF 2.3, C-
3), 159.2 (d, 1JCF 246.8, C-6); δF -140.4 (1 F, dd, 3JFF 24.1, 4JFF 24.1, F-4), -94.0 (1 F, dd, 4JFF 31.0, 5JFF
24.1, F-6), -85.5 (1 F, dd, 3JFF 29.8, 5JFF 24.1, F-3); m/z (ES+) 241.2 ([MH]+, 100%).
25

ACCEPTED MANUSCRIPT
4-(Ethylthio)-3,5,6-trifluoropyridazine 2k
Tetrafluoropyridazine 1 (780 mg, 5.13 mmol), DIPEA (1.35 mL, 7.73 mmol), ethanethiol (0.30 mL, 4.1
mmol) and THF (10 mL) after stirring at 0 °C for 1 h gave 4-(ethylthio)-3,5,6-trifluoropyridazine 2k
3
5
3
(514 mg, 65%) as a colourless oil; δH 3.27 (2 H, qt, JHH 7.4, JHF 1.1, CH2), 1.40 (3 H, t, JHH 7.4,
4
CH3); δF -74.6 (1F, dd, 3JFF 30.2, JFF 21.0, F-5), -99.4 (1 F, dd, 3JFF 30.2, 5JFF 26.4, F-6), -124.8 (1 F,
dd, 5JFF 26.4, 4JFF 21.0, F-3); m/z (AP+) 195.0210 (C6H6N2F3S requires 195.0204).
3,6-Difluoro-4,5-bis(phenylthio)pyridazine 2l
Tetrafluoropyridazine 1 (780 mg, 5.13 mmol), DIPEA (2.6 mL, 14.8 mmol), thiophenol (1 mL, 9.7
mmol) and THF (10 mL) after stirring at rt overnight gave 3,6-difluoro-4,5-bis(phenylthio)pyridazine
2l (1314 mg, 77%) as yellow crystals; mp 99.1 – 100.3 °C (Found: C, 57.7; H, 3.0; N, 8.3.
C16H10F2N2S2 requires: C, 57.8; H, 3.0; N, 8.4%); νmax/cm-1 1578, 1500 and 1377; δH 7.34 - 7.47 (10 H,
2
3
m, CH); δC 129.3 (s, C-4’), 129.6 (s, C-3’), 130.2 (s, C-1’), 132.2 (s, C-2’), 133.6 (dd, JCF 17.5, JCF
15.9, C-4), 162.6 (dd, 1JCF 249.2, 4JCF 6.3, C-3); δF -75.8 (br s); m/z (ES+) 333.2 ([MH]+, 100%).
3,4,6-Trifluoro-5-phenylpyridazine 2m
Tetrafluoropyridazine (780 mg, 5.13 mmol), phenylmagnesium bromide (1M solution in THF, 5.13
mL, 5.13 mmol) and THF (10 mL) under nitrogen at -78 °C and warmed to rt for 16 h and
recrystallisation from cyclohexane gave 3,4,6-trifluoro-5-phenylpyridazine 2m (501 mg, 47%) as white
crystals; m.p. 82.7 – 83.4 °C (Found: C, 57.1; H, 2.4; N, 13.2. C10H5F3N2 requires: C, 57.1; H, 2.4; N,
2
13.3%); νmax/cm-1 1580, 1558, 1458 and 1445; δH 7.56 - 7.62 (5 H, m, CH); δC 121.2 (ddd, JCF 31.9,
3
2JCF 8.7, JCF 4.0, C-5), 123.6 (br s, C-4’), 129.0 (s, C-2’), 129.7 (br s, C-3’), 131.1 (s, C-1’), 147.8
1
2
3
1
4
(ddd, JCF 281.2, JCF 27.1, JCF 7.9, C-4), 156.5 (ddd, JCF 243.6, 3JCF 12.7, JCF 2.4, C-6), 162.30 (d,
1JCF 245.2, C-3); δF -129.3 (1 F, dd, 3JFF 26.4, 4JFF 21.8, F-4), -97.6 (1 F, dd, 5JFF 31.0, 3JFF 26.4, F-3), -
79.6 (1 F, dd, 5JFF 31.0, 4JFF 21.8, F-6); m/z (ES+) 211.2 ([MH]+, 100%).
Reactions of Trifluoropyridazine derivatives
General procedure
26

ACCEPTED MANUSCRIPT
A mixture consisting of DIPEA, nucleophile, trifluorophenylpyridazine and THF was heated and
stirred as approprite. The mixture was concentrated in vacuo, partitioned between EtOAc (20 mL) and
water (20 mL) and the aqueous phase was further extracted with EtOAc (2 x 20 mL). The combined
organic phases were concentrated in vacuo and dried (MgSO4). Column chromatography on silica gel
gave the difunctional difluoropyridazine product.
4-(3,6-Difluoro-5-phenyl-4-pyridazinyl)morpholine 3a
DIPEA (0.18 mL, 1.03 mmol), morpholine (0.06 mL, 0.68 mmol), 3,4,6-trifluoro-5-phenylpyridazine
2m (143 mg, 0.680 mmol) and THF (10 mL) after stirring at rt for 4 d and column chromatography on
silica gel using a 5-25% THF in cyclohexane gradient as eluent gave 4-(3,6-difluoro-5-phenyl-4-
pyridazinyl)morpholine 3a (61 mg, 32 %) as white crystals; mp 180.6 – 182.0 °C (Found: C, 60.5; H,
4.7; N, 15.0. C10H5F3N2 requires: C, 60.6; H, 4.7; N, 15.1%); νmax/cm-1 2977, 2857 and 1543; δH 3.04
(4 H, td, 3JHH 4.7, 5JHF 1.6, NCH2), 3.61 (4 H, dd, 3JHH 4.8, 3JHH 4.6, OCH2), 7.31 - 7.38 (2 H, m, CH),
7.42 - 7.57 (3 H, m, CH); δC 50.5 (d, 4JCF 4.8, NCH2), 66.5 (s, OCH2), 120.2 (dd, 2JCF 31.2, 3JCF 6.4, C-
5), 128.9 (s, C-2’), 129.4 (s, C-3’), 129.5 (br s, C-4’), 129.6 (t, 3JCF 2.4, C-1’), 139.2 (dd, 2JCF 22.4, 3JCF
1
6.4, C-4), 159.3 (d, JCF 240.5, C-3), 163.3 (d, 1JCF 239.7, C-6); δF -86.9 (1 F, d, 5JFF 31.6, F-3), -84.0
(1 F, d, 5JFF 31.6, F-6); m/z (ES+) 278.2 ([MH]+, 100%).
4-{3,6-Difluoro-5-[(1-methylethyl)oxy]-4-pyridazinyl}morpholine 3b
Method A: DIPEA (0.20 mL, 1.15 mmol), morpholine (0.07 mL, 0.80 mmol), 3,4,6-trifluoro-5-[(1-
methylethyl)oxy]pyridazine 2l (153 mg, 0.80 mmol) and THF (10 mL) after stirring at rt for 4 d and
column chromatography on silica gel using a 5-25% THF in cyclohexane gradient as eluent gave 4-
{3,6-difluoro-5-[(1-methylethyl)oxy]-4-pyridazinyl}morpholine 3b (163 mg, 79 %) as white crystals;
mp 73.9 – 75.4 °C (Found: [MH]+, 260.12041. C11H15F2N3O2 requires: [MH]+, 260.12051); νmax/cm-1
2980, 2861, 1566; δH 1.33 (6 H, d, 3JHH 6.2, CH3), 3.39 (4 H, dd, 3JHH 4.4, 5JHF 3.3, NCH2), 3.76 (4 H,
3
3
5
4
t, JHH 4.4, OCH2), 4.63 - 4.76 (1 H, m, JHH 6.2, JHF 1.4, CH); δC 22.3 (s, CH3), 50.4 (d, JCF 4.8,
NCH2), 66.9 (s, OCH2), 77.1 (d, 4JCF 5.6, CH), 133.2 (dd, 2JCF 23.2, 3JCF 8.0, C-4), 137.0 (dd, 2JCF 24.8,
1
1
5
3JCF 8.8, C-5), 159.5 (d, JCF 239.7, C-3), 160.4 (d, JCF 240.5, C-6); δF -93.2 (1 F, d, JFF 29.8, F-6), -
86.2 (1 F, d, 5JFF 29.8, F-3); m/z (ES+) 260.3 ([MH]+, 100%).
27

ACCEPTED MANUSCRIPT
Method B: Lithium isopropoxide (2 M in THF, 0.45 mL, 0.90 mmol), 4-(3,5,6-trifluoro-4-
pyridazinyl)morpholine 2a (195 mg, 0.89 mmol) and THF (10 mL) at -78 °C, stirring for 16 h at rt
overnight and column chromatography on silica gel using a 2-13% EtOAc in toluene gradient as eluent
gave 4-{3,6-difluoro-5-[(1-methylethyl)oxy]-4-pyridazinyl}morpholine 3b (94 mg, 41%) as white
crystals; physical and spectroscopic data as above.
4-(5-(Ethylthio)-3,6-difluoropyridazin-4-yl)morpholine 3c
DIPEA (0.27 mL, 1.5 mmol), morpholine (0.09 mL, 1.03 mmol), 4-(ethylthio)-3,5,6-
trifluoropyridazine 2k (200 mg, 1.03 mmol) and THF (10 mL) after stirring at rt for 16 h and column
chromatography on silica gel using hexane as eluent gave 4-(5-(ethylthio)-3,6-difluoropyridazin-4-
yl)morpholine 3c (197 mg, 73%) as a yellow oil; (Found: C, 45.6; H, 5.1; N, 16.2. C10H13F2N3OS
requires: C, 45.9; H, 5.0; N, 16.1%); νmax/cm-1 2965, 2853, 1638 and 1546; δH 1.29 (3 H, td, 3JHH 7.4,
6JHF 0.5, CH3), 3.09 (2 H, qd, 3JHH 7.4, 5JHF 1.6, SCH2), 3.41 (4 H, td, 3JHH 4.7, 5JHF 2.3, NCH2), 3.84 (4
3
5
4
4
H, t, JHH 4.7, OCH2); δC 14.9 (d, JCF 0.9, CH3), 28.5 (d, JCF 8.9, SCH2), 51.0 (d, JCF 4.6, NCH2),
67.1 (d, 5JCF 1.5, OCH2), 121.3 (dd, 2JCF 32.6, 3JCF 6.8, C-4), 140.9 (dd, 2JCF 23.4, 3JCF 7.1, C-5), 159.5
(dd, 1JCF 243.2, 4JCF 1.5, C-6), 164.7 (d, 1JCF 237.9, C-3); δF -88.4 (1 F, d, 5JFF 31.2, F-3), -78.5 (1 F, d,
5JFF 31.2, F-6); m/z (ES+) 260.9 ([M]+, 100%).
3,6-Difluoro-4-phenyl-5-(phenylthio)pyridazine 3d
DIPEA (0.19 mL, 1.1 mmol), thiophenol (0.07 mL, 0.68 mmol), 3,4,6-trifluoro-5-phenylpyridazine 2m
(150 mg, 0.714 mmol) and THF (10 mL) after stirring at 0 °C for 1 hour and column chromatography
on silica gel using 1-7% THF in cyclohexane gradient as eluent gave 3,6-difluoro-4-phenyl-5-
(phenylthio)pyridazine 3d (188 mg, 88%) as off-white crystals; mp 78.9 – 80.0 °C (Found: C, 64.0; H,
3.4; N, 9.3. C16H10F2N2S2 requires: C, 64.0; H, 3.4; N, 9.3%); νmax/cm-1 1523, 1443 and 1386; δH 7.20 -
7.31 (5 H, m, ArH), 7.33 - 7.40 (2 H, m, ArH), 7.44 - 7.55 (3 H, m, ArH); δC 128.6 (s, C-2’), 128.8 (d,
3JCF 2.4, C-1’), 128.9 (s, C-4’’), 129.3 (s, C-3’’), 129.4 (s, C-3’), 130.1 (s, C-4’), 130.3 (d, 4JCF 2.4, C-
1’’), 132.0 (s, C-2’’), 132.4 (dd, 2JCF 29.6, 3JCF 4.0, C-4), 134.5 (dd, 2JCF 31.2, 3JCF 3.2, C-5), 162.1 (d,
1JCF 245.3, C-6), 163.3 (d, 1JCF 244.5, C-3); δF -83.3 (1 F, d, 5JFF 31.0, F-3), -75.3 (1 F, d, 5JFF 31.0, F-
6); m/z (ES+) 301.2 ([MH]+, 100%).
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