Nucleophilic aromatic substitutions on 4,5-dicyanopyridazine. Part 2: Nitrogen nucleophiles

Article abstract of DOI:10.1016/j.tet.2013.02.052

As previously reported with pyrrole and indole C-nucleophiles, 4,5-dicyanopyridazine (DCP) showed remarkable reactivity as a heterocyclic electrophile at the C-4 carbon toward amino nucleophiles. Aminocyanopyridazines, the formal S_NAr2 products, have been easily synthesized in satisfactory yields through the facile substitution of a CN group of DCP, that behaves as leaving group. Operating in different solvents, the best results were generally obtained with a medium polar solvent, such as THF. The introduction of amino functionalities into the pyridazine system allows a desymmetrization of the starting material and opens the way to further synthetic elaborations.

Full text of DOI:10.1016/j.tet.2013.02.052

Tetrahedron 69 (2013) 3475e3479
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Nucleophilic aromatic substitutions on 4,5-dicyanopyridazine.
Part 2: Nitrogen nucleophiles
*
Renzo Alfini, Elisa Calamai, Antonella Salvini, Donatella Giomi
ꢀ
Dipartimento di Chimica ‘Ugo Schiff’, Universita di Firenze, Polo Scientifico e Tecnologico, Via della Lastruccia 3-13, I-50019 Sesto Fiorentino, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
As previously reported with pyrrole and indole C-nucleophiles, 4,5-dicyanopyridazine (DCP) showed
remarkable reactivity as a heterocyclic electrophile at the Ce4 carbon toward amino nucleophiles.
Aminocyanopyridazines, the formal SNAr2 products, have been easily synthesized in satisfactory yields
through the facile substitution of a CN group of DCP, that behaves as leaving group. Operating in different
solvents, the best results were generally obtained with a medium polar solvent, such as THF. The in-
troduction of amino functionalities into the pyridazine system allows a desymmetrization of the starting
material and opens the way to further synthetic elaborations.
Received 30 November 2012
Received in revised form 29 January 2013
Accepted 18 February 2013
Available online 26 February 2013
Keywords:
Pyridazines
Ó 2013 Elsevier Ltd. All rights reserved.
Cyanopyridazines
Cyano heterocycles
Nucleophilic aromatic substitutions
Nitrogen nucleophiles
Aminopyridazines
1. Introduction
reported. Concerning 1,2-diazines, in particular, apart from pre-
liminary data relating to reactions of 1-phthalazine- and 4-
In the domain of drug molecules, recent literature data showed
that the bioisosteric replacement of phenyl rings with the corre-
sponding pyridazine nucleus opens the way to diaza analogues
characterized by significant improvements with respect to receptor
interactions, metal coordination, salt formation, and water solu-
bility.1 Due to their affinity for a great number of receptor proteins,
pyridazines can be certainly considered as ‘privileged structures’ in
medicinal chemistry,1 according to Evans’s definition.2 In this
context, aminopyridazine derivatives play a very important role
confirmed by the presence of this pharmacophoric moiety in nat-
ural and bioactive compounds,1 such as dopaminergic, serotoner-
gic, cholinergic ligands, monoamine oxidase, and acetylcholine
esterase inhibitors,3 orally active antinociceptive agents,4 as well as
suppressors of glial activation involved in neurodegenerative dis-
orders such as Alzheimer’s disease.5
cinnoline-carbonitriles with Grignard reagents,11 the nucleophilic
substitution of the CN group has been clearly observed only in the
treatment of cinnoline-3,4-dicarbonitrile with ammonia and
amines12 and in the reactions of 4-cyano-3(2H)-pyridazinone and
tetrazolo[1,5-b]pyridazine-8-carbonitrile with phenylmagnesium
chloride.13
Previous studies from our laboratory showed 4,5-
dicyanopyridazine (DCP) (1) displayed surprising reactivity as
a
heterocyclic azadiene in inverse electron-demand Hetero
DielseAlder (HDA) reactions with different dienophiles, allowing
facile access to functionalized mono- and polycyclic systems.14
Furthermore, recent results showed for compound 1 an un-
precedented behavior as a very reactive heterocyclic electrophile at
the C-4 carbon atom. Depending on the reaction conditions, DCP is
able to react with pyrrole and indole counterparts as an azadiene,
affording benzoannelated pyrrole and indole systems,15 as well as
an electrophile. In the latter case, cyanopyrrolyl- and cyanoindolyl-
pyridazines have been easily synthesized through formal SNAr2
processes where pyrrole and indole derivatives act as carbon nu-
cleophiles displacing a CN group of DCP.16 With the aim of evalu-
ating the applications and limits of this new facet of reactivity of
DCP, we decided to investigate its behavior as a heterocyclic elec-
trophile toward different nitrogen nucleophiles, which would
provide direct access to aminopyridazine derivatives.
On the other hand, nucleophilic displacement of a cyano group
in cyano substituted heterocycles is quite unusual and only a few
examples involving 1,2,4-triazine-,6 quinazoline-,6b,7 pyrazine-,8 as
well as pyridine-9 and pyridinium-carbonitriles10 have been
* Corresponding author. Tel.: þ39 055 4573475; fax: þ39 055 4573531; e-mail
address: donatella.giomi@unifi.it (D. Giomi).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.052

3476
R. Alfini et al. / Tetrahedron 69 (2013) 3475e3479
2. Results and discussion
polar solvent, such as MeCN, to favor the nucleophilic substitution
processes due to the more efficient stabilization of the Mei-
senheimer intermediates I and then of the near transition states.
The dinitrile 1 was allowed to react with different primary and
secondary amines. The reactions were first performed using chlo-
roform as the solvent, at room temperature and with stoichiometric
amounts of amine 2aee, leading to 5-amino-4-cyanopyridazines
3aee in 41e80% yields (Table 1, entries 1, 3, 5, 7, 9).
More hindered amines, such as diisopropylamine 2f and dia-
llylamine 2g, were less reactive and so the reactions were per-
formed with an excess of reagents (3 equiv) at 50 ꢀC, for longer
times, affording compounds 3f and 3g in 13 and 48% yields, re-
spectively (Table 1, entries 11 and 16). Due to these poor results (in
particular with 2f), the above reactions were repeated in a more
CN
N
NHR1R2
CN
N
I
Operating with a stoichiometric amount of diisopropylamine 2f,
at room temperature, aminopyridazine 3f was isolated in 35% yield
(Table 1, entry 12) while no improvements were observed for 2g
(Table 1, entry 17).
Table 1
Reactions of DCP (1) with primary and secondary amines 2aei
CN
N
CN
HCN
N
N
+ R1R2NH
N
CN
NR1R2
1
2
3
Entry
Reagent
Equiv
Solvent
Temp
Time
Product
Yielda (%)
CN
N
N
1
2
1.1
1.1
CHCl3
THF
rt
rt
0.5 h
5 h
65
H2N
N
H
2a
100
3a
CN
N
N
3
4
1.1
1.1
CHCl3
THF
rt
rt
0.5 h
7 h
80
N
H
N
100
2b
3b
CN
N
N
5
6
1.1
1.5
CHCl3
THF
rt
0.5 h
5 h
41
50
HN
N
65 ꢀC
2c
3c
CN
N
N
7
8
1.1
1.1
CHCl3
THF
rt
5 h
51
64
NMe
O
HN
NMe
O
N
65 ꢀC
11 h
2d
2e
3d
CN
N
N
9
1.1
1.5
3
CHCl3
THF
rt
24 h
5 h
47
72
13
HN
N
10
11
65 ꢀC
50 ꢀC
3e
CHCl3
72 h
CN
N
N
N
N
H
12
13
14
15
1.1
1.1
1.1
1.1
MeCN
DMF
THF
rt
rt
rt
65 ꢀC
42 h
63 h
48 h
5 d
35
18
db
dc
2f
THF
3f
CN
N
N
16
3
CHCl3
50 ꢀC
25 h
48
H
N
N
17
18
1.1
1.5
MeCN
THF
rt
72 h
50 h
17
110 ꢀCd
30e
2g
3g

R. Alfini et al. / Tetrahedron 69 (2013) 3475e3479
3477
Table 1 (continued )
Entry
Reagent
Equiv
1.5
Solvent
THF
Temp
Time
82 h
Product
Yielda (%)
CN
N
N
NH2
19
20
110 ꢀCd
78
96
N
H
3h
2h
2i
CN
N
N
110 ꢀCd
60 h
NH2
1.5
THF
N
H
3i
a
Isolated yields.
No reactivity.
b
c
Complex reaction mixture containing both DCP and 3f.
Reactions performed in a screw-cap tube (Pyrex Nꢀ 13).
Yield based on the recovery of unreacted 1.
d
e
To evaluate the solvent effect, the reaction of 2f with DCP was
Even less reactive aromatic amines, such as aniline (2h) and p-
toluidine (2i), were able to react with DCP in THF but at higher
temperature and for longer reaction times. These reactions were
then performed in a screw-cap Pyrex tube, by simple heating a THF
solution of both the reagents at 110 ꢀC, leading to the formation of
derivatives 3h,i in 78 and 96% yields, respectively (Table 1, entries
19 and 20).
On the basis of the previous results obtained with pyrrole and
indole C-nucleophiles,16 providing evidence for the formation of
1,4-dihydropyridazine intermediates, the formation of nucleophilic
aromatic substitution products 3aei is likely the result of an
additioneelimination (AeE) mechanism (Scheme 1). Certainly, in
this case, the use of basic reagents strongly favors the HCN elimi-
nation step, that gives rise to aromatic derivatives, preventing the
isolation of 1,4-dihydropyridazine adducts of type 4.
studied in a highly polar solvent (DMF) and a less polar solvent
(THF). Unfortunately, in the former case compound 3f was isolated
in only 18% yield from a complex reaction mixture (Table 1, entry
13) and in the latter DCP was absolutely inert toward 2f at room
temperature while, after heating at 65 ꢀC for five days, a complex
mixture was obtained preventing the isolation of the reaction
product (Table 1, entries 14 and 15). In the case of 2g the reaction
rate in THF was very low at 65 ꢀC and so the reaction was then
performed at 110 ꢀC, in a screw-cap Pyrex tube, but compound 3g
was isolated in only 30% yield (Table 1, entry 18).
These reactions were often characterized by the formation of
complex reaction mixtures containing black residues, insoluble for
the most part in organic solvents, likely associated with polymer-
ization and/or decomposition processes. Scarcely reactive nucleo-
philes and highly polar solvents can then favor nucleophilic attacks
CN
CN
NR1R2
CN
CN
N
N
HN
N
HCN
N
N
+ R1R2NH
CN
NR1R2
1
2
4
3
Scheme 1. Proposed reaction mechanism.
of the Meisenheimer intermediates I on the highly electrophilic
DCP, leading to disappearance of the starting pyridazine without
significant formation of substitution products.
3. Conclusions
In conclusion, these results clearly show that DCP (1) displays
remarkable reactivity as a heterocyclic electrophile toward amino
counterparts. Aminocyanopyridazines 3aei have been easily
synthesized in satisfactory yields from the starting pyridazine,
confirming the facile substitution of a CN group that behaves as
leaving group. On the other hand, the CN group in derivatives
3aei, certainly due to the presence of the amino function, is no
longer activated toward nucleophilic substitution and as such the
reaction products are stable even in the presence of an excess of
nucleophile. Performing the above reactions in different solvents,
apart from a few cases, the best results were obtained with
a medium polar solvent, such as THF, through a slow addition of
DCP to disfavor competing reactions. The introduction of amino
functionalities into the pyridazine skeleton appears very prom-
ising from both synthetic and biological viewpoints: in fact, it
allows a desymmetrization of the starting material and makes
possible further synthetic elaborations, especially oriented to the
synthesis of bioactive compounds. In particular, the use of
Despite the problems observed in the reactions of DCP with 2f
and 2g in tetrahydrofuran, with all the other tested amines the use
of THF, at room temperature or under heating, led to improved
results. In particular, when a solution of DCP in THF was slowly
added to a solution of the amine (in almost stoichiometric amount)
in the same solvent, the reaction rates were decreased with respect
to the corresponding reactions in chloroform but this drawback
was balanced by the achievement of cleaner reactions from which
the substitution products were more easily recovered and in higher
yields. This procedure guarantees a low concentration of DCP in the
solution and this situation seems to promote the nucleophilic at-
tack of the amino reagent on 1, disfavoring the competitive poly-
merization/decomposition processes. Following this procedure,
compounds 3a,b were isolated in quantitative yields operating at
room temperature for 5e7 h (Table 1, entries 2 and 4) while 3cee
were recovered in 50e72% yields, by heating for 5e11 h at 65 ꢀC
(Table 1, entries 6, 8, 10).

3478
R. Alfini et al. / Tetrahedron 69 (2013) 3475e3479
suitable bis-nucleophiles could open the way to the synthesis of
new condensed polynuclear pyridazine derivatives. The study of
synthetic applications of this new methodology is now in prog-
ress in our laboratory.
(m, 4H, 30-CH2 and 40-CH2); 13C NMR (CDCl3)
140.8 (d), 117.3 (s), 90.4 (s), 49.2 (t), 25.1 (t).
(B) Operating for 7 h at room temperature, compound 3b
(87.0 mg, 100%) was recovered by evaporation to dryness of the
ethereal solution.
d 151.3 (d), 142.4 (s),
4. Experimental section
4.1. General
4.2.3. Reactions of DCP (1) with piperidine (2c). (A) After 0.5 h, the
mixture obtained from DCP and 2c (46.8 mg, 54 mL, 0.55 mmol) was
subjected to FC resolution (EtOAc) affording 4-cyano-5-(piperidin-
1-yl)pyridazine (3c) (39.0 mg, 41%) as a brown solid, Rf (EtOAc) 0.21,
mp 116e117 ꢀC (from Et2O/PE); [found: C, 63.53; H, 6.21; N, 29.56.
C10H12N4 requires: C, 63.81; H, 6.43; N, 29.77]. IR (KBr) 3060, 2925,
Melting points were taken on a Stuart Scientific SIMP3 appa-
ratus and are uncorrected. Silica gel plates (Merck F254) and silica
gel 60 (Merck, 230e400 mesh) were used for TLC and flash chro-
matographies (FC), respectively. Petroleum ether (PE) employed for
crystallizations and chromatographic workup refers to the fractions
of bp 30e50 and 40e70 ꢀC, respectively. IR spectra were recorded
with a PerkineElmer Spectrum BX FT-IR System spectrophotome-
ter. 1H and 13C NMR spectra were recorded with a Varian Mercu-
ryplus 400 instrument, operating at 400 and 100 MHz, respectively.
Elemental analyzes were performed with a PerkineElmer 2400
analyzer. Accurate mass spectra were recorded on a LTQ-Orbitrap
high-resolution mass spectrometer (Thermo, San Jose, CA, USA),
equipped with a conventional ESI source.
2856, 2212,1560 cmꢁ1; 1H NMR (acetone-d6)
d
9.02 (d, J¼0.7 Hz,1H,
H-6), 8.70 (d, J¼0.7 Hz, 1H, H-3), 3.83e3.81 (m, 4H, 20-CH2 and 60-
CH2), 1.78e1.75 (m, 6H, 30-CH2, 40-CH2 and 50-CH2); 13C NMR (ac-
etone-d6)
d 152.2 (d), 146.3 (s), 143.0 (d), 117.7 (s), 93.2 (s), 49.8 (t),
26.4 (t), 24.4 (t).
(B) Operating for 5 h at 65 ꢀC with 1.5 equiv of 2c (63.9 mg, 74
mL,
0.75 mmol), chromatographic separation afforded 3c (47.0 mg,
50%).
4.2.4. Reactions of DCP (1) with N-methylpiperazine (2d). (A) After
DCP was allowed to react with 2d (55.1 mg, 61 mL, 0.55 mmol) for
5 h, FC separation (EtOAc/MeOH/Et3N 90:5:5) gave 4-cyano-5-(4-
methylpiperazin-1-yl)pyridazine (3d) (52.0 mg, 51%) that crystal-
lized from Et2O/PE in orange needles, Rf (EtOAc/MeOH/Et3N 90:5:5)
0.18, mp 122e123 ꢀC; [found: C, 58.79; H, 6.25; N, 34.12. C10H13N5
requires: C, 59.10; H, 6.45; N, 34.46]. IR (KBr) 3067, 2940, 2804,
4.2. Reactions of DCP (1)14 with amines 2aee. General
procedures
(A) A mixture of DCP (1) (65.0 mg, 0.50 mmol) and the amine
(0.55 mmol) in CHCl3 (1 mL) was kept at room temperature
under magnetic stirring in a screw-cap tube (Pyrex N. 13) for the
reported time. Chromatographic purification of the crude re-
action mixture obtained by evaporation of the solvent under
reduced pressure, allowed the isolation of the aminopyridazine
derivative.
2216, 1574 cmꢁ1; 1H NMR (CDCl3)
d
8.88 (d, J¼0.7 Hz, 1H, H-6), 8.73
(d, J¼0.7 Hz, 1H, H-3), 3.80 (t, J¼5.1 Hz, 4H, 20-CH2 and 60-CH2), 2.60
(t, J¼5.1 Hz, 4H, 30-CH2, and 50-CH2), 2.36 (s, 3H, NCH3); 13C NMR
(CDCl3)
(t), 45.7 (q).
(B) After heating at 65 ꢀC for 11 h, FC resolution led to 3d
d 151.7 (d),145.5 (s), 141.7 (d), 116.4 (s), 93.8 (s), 54.3 (t), 47.8
(B) Unless otherwise stated, operating with the same amounts
of reagents, a solution of DCP in anhydrous THF (4 mL) was
slowly added (ca. 1 h) to a solution of the amine in the same
solvent (1 mL). The resulting solution was kept at room tem-
perature or heated to reflux under magnetic stirring for the re-
ported time.
(65.0 mg, 64%).
4.2.5. Reactions of DCP (1) with morpholine (2e). (A) After reaction
of DCP with 2e (47.9 mg, 48 mL, 0.55 mmol) for 24 h, chromato-
graphic separation (EtOAc/MeOH 95:5) afforded 4-cyano-5-
morpholinopyridazine (3e) (45.0 mg, 47%) as a red solid, Rf
(EtOAc/MeOH 95:5) 0.29, mp 168e169 ꢀC (from Et2O/CHCl3);
[found: C, 56.89; H, 5.52; N, 29.77. C9H10N4O requires: C, 56.83; H,
5.30; N, 29.46]. IR (KBr) 3070, 2970, 2924, 2219,1563 cmꢁ1; 1H NMR
4.2.1. Reactions of DCP (1) with n-propylamine (2a). (A) After 0.5 h,
chromatographic resolution (PE/EtOAc 1:5) of the reaction mixture
obtained from DCP and 2a (32.5 mg, 45
m
L, 0.55 mmol) allowed the
(acetone-d6)
d
9.08 (d, J¼0.8 Hz, 1H, H-6), 8.78 (d, J¼0.8 Hz, 1H, H-
isolation of 4-cyano-5-propylaminopyridazine (3a) (53.0 mg, 65%)
as a pale yellow solid, Rf (PE/EtOAc 1:5) 0.31, mp 100e101 ꢀC (from
Et2O/acetone); [found: C, 59.03; H, 6.01; N, 34.74. C8H10N4 requires:
C, 59.24; H, 6.21; N, 34.54%]. IR (KBr) 3232, 3172, 3030, 2967, 2862,
3), 3.86 (s, 8H, 20-CH2, 30-CH2, 50-CH2, and 60-CH2); 13C NMR (ace-
tone-d6)
d 152.1 (d), 146.7 (s), 142.9 (d), 117.5 (s), 94.1 (s), 66.8 (t),
48.7 (t).
(B) Operating for 5 h at 65 ꢀC with 1.5 equiv of 2e (65.3 mg, 66
mL,
2219, 1610, 1587 cmꢁ1; 1H NMR (CDCl3)
d
8.84 (s, 1H, H-6), 8.70 (br
0.75 mmol), chromatographic separation afforded 3e (68.7 mg, 72%).
s, 1H, H-3), 5.86 (br s, 1H, NH), 3.45e3.40 (m, 2H, NCH2CH2CH3),
1.75 (sextet, J¼7.3 Hz, 2H, NCH2CH2CH3), 1.04 (t, J¼7.3 Hz, 3H,
4.3. Reactions of DCP (1) with amines 2fei. General procedure
NCH2CH2CH3); 13C NMR (CDCl3)
d
149.5 (d),17 145.1 (s), 138.7 (d),17
114.1 (s), 92.3 (s),17 44.4 (t), 22.4 (t), 11.1 (q).
(B) Operating for 5 h at room temperature, compound 3a
(81.0 mg, 100%) was recovered by evaporation to dryness of the
ethereal solution.
A mixture of DCP (1) (65.0 mg, 0.50 mmol) and the amine in the
reported solvent (1 mL) was kept at the specified temperature
under magnetic stirring in a screw-cap tube (Pyrex N. 13) for the
reported time. Chromatographic resolution of the crude reaction
mixture obtained by evaporation of the solvent under reduced
pressure allowed the isolation of the corresponding amino-
pyridazine derivative.
4.2.2. Reactions of DCP (1) with pyrrolidine (2b). (A) After 0.5 h, FC
separation (PE/EtOAc 1:1) of the crude reaction mixture obtained
from DCP and 2b (39.1 mg, 46 mL, 0.55 mmol) afforded 4-cyano-5-
(pyrrolidin-1-yl)pyridazine (3b) (70.0 mg, 80%) that crystallized
from Et2O/acetone as pale yellow needles, Rf (PE/EtOAc 1:1) 0.34,
mp 160e161 ꢀC; [found: C, 61.79; H, 5.76; N, 32.02. C9H10N4 re-
quires: C, 62.05; H, 5.79; N, 32.16]. IR (KBr) 3065, 3028, 2981, 2950,
4.3.1. Reaction of DCP (1) with diisopropylamine (2f). FC resolution
(EtOAc/MeOH 20:1) of the crude obtained by treatment of DCP with
amine 2f (55.6 mg, 77 mL, 0.55 mmol) in MeCN at room temperature
for 42 h, led to 4-cyano-5-diisopropylaminopyridazine (3f)
(36.0 mg, 35%) as a brown sticky product, Rf (EtOAc/MeOH 20:1)
0.33. IR (KBr) 3070, 2972, 2920, 2229, 1608 cmꢁ1; 1H NMR (DMSO-
2875, 2215, 1571, 1553, 1453 cmꢁ1; 1H NMR (CDCl3)
d
8.63e8.62 (m,
2H, H-3 and H-6), 3.82e3.67 (m, 4H, 20-CH2 and 50-CH2), 2.09e2.06

R. Alfini et al. / Tetrahedron 69 (2013) 3475e3479
3479
d6)
d
8.31 (d, J¼0.7 Hz, 1H, H-3), 8.08 (d, J¼0.7 Hz, 1H, H-6), 3.29
4.89; N, 26.72. C12H10N4 requires: C, 68.56; H, 4.79; N, 26.65]. IR
(KBr) 3221, 3116, 2914, 2223, 1605, 1560 cmꢁ1 1H NMR (acetone-
d6)
8.88 (d, J¼0.8 Hz, 1H, H-6), 8.84 (d, J¼0.8 Hz, 1H, H-3), 8.79 (br
s, 1H, NH), 7.32 (s, 4H, Are4H), 2.38 (s, 3H, CH3); 13C NMR (acetone-
d6) 151.2 (d), 144.9 (s), 141.0 (d), 137.7 (s), 135.1 (s), 131.1 (d), 125.7
(septet, J¼6.5 Hz, 2H, 2ꢂ CH), 1.22 (d, J¼6.5 Hz, 12H, 4ꢂ CH3); 13C
;
NMR (DMSO-d6)
d
166.9 (s), 152.1 (d), 150.8 (d), 118.5 (s), 96.2 (s),
d
46.2 (d), 18.9 (q). HRMS (ESI): MHþ, found 205.1445, C11H17N4 re-
quires 205.1448.
d
(d), 114.8 (s), 93.9 (s), 21.0 (q).
4.3.2. Reaction of DCP (1) with diallylamine (2g). Operating in
CHCl3 at 50 ꢀC for 25 h with 3 equiv of 2g (145.7 mg, 185
mL,
Acknowledgements
1.50 mmol), 4-cyano-5-diallylaminopyridazine (3g) (48.1 mg, 48%)
was isolated by FC resolution (PE/EtOAc 2:3) as an orange oil, Rf (PE/
Mrs. B. Innocenti and Mr. M. Passaponti are acknowledged for
technical support. The authors thank the Centro Inter-
dipartimentale di Spettrometria di Massa (CISM) of the University
of Firenze for the HRMS analyzes and the Ente Cassa di Risparmio di
Firenze for the grant of the Varian Mercuryplus 400 instrument.
EtOAc 2:3) 0.33. IR (liquid film) 3085, 2927, 2218, 1566 cmꢁ1 1H
;
NMR (CDCl3)
d
8.75 (d, J¼0.8 Hz, 1H, H-6), 8.68 (d, J¼0.8 Hz, 1H, H-
3), 5.94e5.85 (ddt, J¼17.2, 10.3 and 4.8 Hz, 2H, 2ꢂ CH2CH]CH2),
5.36e5.33 (m, 2H, 2ꢂ CH2CH]CH2), 5.23e5.18 (m, 2H, 2ꢂ CH2CH]
CH2), 4.24e4.22 (m, 4H, 2ꢂ CH2CH]CH2); 13C NMR (CDCl3)
d 152.0
(d), 143.9 (s), 140.7 (d), 130.4 (d), 118.5 (t), 116.9 (s), 90.8 (s), 52.8 (t).
References and notes
HRMS (ESI): MHþ, found 201.1132, C11H13N4 requires 201.1135.
1. Wermuth, C.-G. Med. Chem. Commun. 2011, 2, 935e941 and references cited
therein.
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17. Broad signal.
4.3.3. Reaction of DCP (1) with aniline (2h). Operating in THF at
110 ꢀC (screw-cap tube Pyrex N. 13) for 82 h with 1.5 equiv of 2h
(69.8 mg, 68
mL, 0.75 mmol), 5-anilino-4-cyanopyridazine (3h)
(76.8 mg, 78%) was isolated by FC resolution (PE/EtOAc 1:1) and
crystallized from PE/acetone as pale orange needles, Rf (PE/EtOAc
1:1) 0.28, mp 186e187 ꢀC; [found: C, 66.99; H, 3.81; N, 28.24.
C11H8N4 requires: C, 67.34; H, 4.11; N, 28.55]. IR (KBr) 3229, 3129,
2227, 1608, 1561 cmꢁ1 1H NMR (acetone-d6)
; d 8.95 (s, 1H, H-6),
8.87 (br s, 2H, H-3 and NH), 7.53e7.49 (m, 2H, Are2H), 7.45e7.44
(m, 2H, Are2H), 7.35 (t, J¼7.4 Hz,1H, Are1H); 13C NMR (acetone-d6)
d
151.2 (d), 144.7 (s), 141.1 (d), 137.8 (s), 130.6 (d), 127.7 (d), 125.5 (d),
114.8 (s), 94.3 (s).
4.3.4. Reaction of DCP (1) with p-toluidine (2i). FC resolution (PE/
EtOAc 1:1) of the reaction crude obtained by heating DCP and p-
toluidine (2i) (80.4 mg, 0.75 mmol) in THF at 110 ꢀC in a screw-cap
tube (Pyrex N. 13) for 60 h gave rise to 4-cyano-5-(4-toluidino)
pyridazine (3i) (101.0 mg, 96%) as ivory flakes, Rf (PE/EtOAc 1:1)
0.35, mp 226e227 ꢀC (from Et2O/acetone); [found: C, 68.21; H,