An electrochemical nickel-catalyzed arylation of 3-amino-6- chloropyridazines

Article abstract of DOI:10.1021/jo3022428

3-Amino-6-aryl- and 3-amino-6-heteroarylpyridazines have been obtained in generally good yield using a nickel-catalyzed electrochemical cross-coupling between 3-amino-6-chloropyridazines and aryl or heteroaryl halides at room temperature. Comparative experiments involving classical palladium-catalyzed reactions, such as Suzuki, Stille, or Negishi cross-couplings, reveal that the electrochemical method can constitute a reliable alternative tool for biaryl formation. A possible reaction mechanism is proposed on the basis of electrochemical analyses.

Full text of DOI:10.1021/jo3022428

Article
pubs.acs.org/joc
An Electrochemical Nickel-Catalyzed Arylation of 3‑Amino-6-
Chloropyridazines
Stephane Sengmany,† Arnaud Vitu-Thiebaud,† Erwan Le Gall,† Sylvie Condon,† Eric Leonel,*,†
́
́
Christine Thobie-Gautier,‡ Muriel Pipelier,‡ Jacques Lebreton,‡ and Didier Dubreuil‡
†Equipe Electrochimie et Synthes
Creteil Val de Marne, 2 rue Henri Dunant, BP 28, F-94320, Thiais, France
‡Laboratoire de Synthes
e Organique, Chimie et Interdisciplinarite: Synthese, Analyse, Model
Nantes, 2 rue de la Houssiniere, BP 92208, F-44322 Nantes Cedex 3, France
̀
e Organique, Institut de Chimie et des Mater
́
iaux Paris-Est, UMR 7182 CNRS-Universite
́
Paris-Est
́
̀
́
̀
́
isation, UMR 6513 CNRS-Universite de
́
̀
S
* Supporting Information
ABSTRACT: 3-Amino-6-aryl- and 3-amino-6-heteroarylpyrida-
zines have been obtained in generally good yield using a nickel-
catalyzed electrochemical cross-coupling between 3-amino-6-
chloropyridazines and aryl or heteroaryl halides at room temper-
ature. Comparative experiments involving classical palladium-
catalyzed reactions, such as Suzuki, Stille, or Negishi cross-
couplings, reveal that the electrochemical method can constitute a reliable alternative tool for biaryl formation. A possible
reaction mechanism is proposed on the basis of electrochemical analyses.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
3-Amino-6-aryl- and 3-amino-6-heteroarylpyridazines have
retained the major attention of the organic community due
to diverse biological activities displayed by these 1,2-
diazaheterocycles, ranging from, for example, anticancer1 or
analgesic effects2 to potential treatment of urinary incon-
tinence,3 inflammatory pain,4 obesity,5 and neurodegenerative
diseases.6 The preparation of aryl- and heteroarylpyridazines
has been mainly described through palladium-catalyzed cross-
coupling strategies, such as Stille7 and Negishi8 reactions.
However, the most widely employed cross-coupling method
remains undoubtedly the Suzuki reaction, due to its general
broad applicability.9 Other original coupling methods have
been investigated as well, and the palladium-catalyzed arylation
of pyridazine N-oxides described by Fagnou and co-workers, a
few years ago, illustrated the purpose.10
In the past years, our group has been involved in several
projects pertaining to the transition-metal-catalyzed electro-
chemical arylation of aryl- and heteroarylhalides. For instance, it
was noticed that a range of azaaromatic and diazaaromatic
halides are efficiently cross-coupled with aryl halides via an
electroreductive procedure employing a nickel foam or an inox
grid11 cathode, a sacrificial iron rod as the anode, and nickel12
or cobalt13 salts as catalyst. Inasmuch as the applicability of the
electrochemical procedure was found to be rather efficient from
several azaheterocycle partners, we envisaged to extend the
process from aminohalopyridazine precursors. This particular
class of bifunctional pyridazines is of interest in regard to their
high potential in therapy (Figure 1).
We focused on the electrochemical cross-coupling of 3-amino-
6-chloropyridazines 1a−1k, prepared following standard
methods,14 with aryl and heteroaryl halides. Although related
cross-coupling reactions had been successfully achieved in our
group starting from halodiazines,15 we considered that the
arylation of 3-amino-6-chloropyridazines was representing a
challenging task, due to the presence of three nitrogen atoms
on the final products.16 In a preliminary experiment, 4-(6-
chloropyridazin-3-yl)morpholine 1a and ethyl 3-bromoben-
zoate were reacted in standard electrochemical conditions,
previously reported by our group:15a the coupling reaction
between the halodiazine (1 equiv) and the aryl halide (2 equiv)
was then run in DMF at room temperature in an undivided
electrochemical cell fitted with an iron rod, surrounded by a
nickel foam as the cathode, in the presence of NiBr2bpy (10
mol %) as catalyst precursor, and tetrabutylammonium
bromide as supporting electrolyte, under a constant current
intensity of 0.2 A (Scheme 1).
Unfortunately, under the latter electrochemical conditions,
the cross-coupling product 2g was only obtained in a moderate
yield (48%). The reaction parameters were then thoroughly
assessed, and the most interesting gathered information
indicated that the replacement of the iron anode by an iron/
nickel (64/36) anode allowed a significant increase of the
reaction yield from 48 to 70%. In this way, nickel salts
generated by the anode consumption may permit the
continuous regeneration of a reactive organonickel species,
thus increasing the efficiency of the nickel-mediated cross-
As a result, we describe herein the nickel-catalyzed
electrochemical arylation of 3-amino-6-chloropyridazines,
using an iron/nickel electrode as the sacrificial anode.
Received: October 12, 2012
© XXXX American Chemical Society
A
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Figure 1. Some biologically active aminoarylpyridazines.
Scheme 1. Model Electrochemical Reaction
coupling reaction. The aryl and heteroaryl halide scope of this
optimized protocol was then evaluated, keeping 4-(6-
chloropyridazin-3-yl)morpholine 1a as the model substrate.
Results are summarized in Table 1.
chloroquinoline, bis-2,2′-quinoline, indicating that, under such
specific substrate conditions, the cross-coupling reaction is not
the favored pathway of the reaction.
The scope of the electrochemical cross-coupling method-
ology was then extended by performing miscellaneous
experiments under the optimized experimental conditions.
Results are reported in Table 2.
Electrochemical cross-coupling reactions generally proceed
in good yields with substituted phenyl halides (entries 1−7,
Table 1). It can be noticed that almost 2 equiv of the halide (vs
3-amino-6-chloropyridazine) is required to complete the
reaction, as illustrated in the case of 3-bromobenzotrifluoride
(entry 5, Table 1). As previously noticed,15a more reactive aryl
iodides are required instead of the bromides when the aryl
moiety is not substituted (entry 1, Table 1) or substituted with
electron-donating groups (entries 2 and 3, Table 1). This is also
the case with a phenyl bearing a fluorine atom (entry 4, Table
1). It was also noticed, in iodides series (entries 1−4, Table 1),
that one additional equivalent of the aryl iodide is generally
required at an intermediate stage of the electrolysis for
completion of the reaction. Indeed, such aryl iodides are, to a
greater extent, prone to reduction and/or dimerization under
these reaction conditions.
Surprisingly, the electrochemical cross-coupling involving a
sterically hindered ortho-substituted aryl bromide allowed the
formation of the target product 2h in a modest 30% yield
(entry 8, Table 1). However, this result constitutes an
interesting feature in favor of the iron/nickel anode, as
inextricable mixtures of reduction and homocoupling side
products were observed in the electrocoupling of 3-chloro-6-
methyl- or 3-chloro-6-methoxypyridazine with ethyl 2-bromo-
benzoate using a conventional iron rod as the anode.15a
Heteroaryl halides (entries 9−11, Table 1) gave also some
interesting results, although more limited yields were generally
expected. With 3-bromothiophene (entry 9, Table 1), the
coupling product 2i was isolated in good yield (71%), whereas
a significant decrease of the yields was observed (around 30%)
when 3-bromopyridine (entry 10, Table 1) and 2-chloroquino-
line (entry 11, Table 1) were employed. These partial failures
rely mainly in the formation of either the hydrodehalogenation
product of 3-bromopyridine or the “dimerization” product of 2-
The results confirm the general efficiency of the electro-
chemical procedure while singular results were obtained in
some specific cases. A very limited yield of 2p (38%) was
obtained starting from 4-bromobenzonitrile (entry 5, Table 2)
as the aryl halide, whereas ethyl 4-bromobenzoate (entry 7,
Table 2) led to a fairly good yield of 2r (60%), thus indicating
that electronic effects are not responsible for the lack of
reactivity of the former. Another singular result was obtained
with a chloropyridazine bearing a diallylamino substituent
(entry 9, Table 2). In this case, no coupling product was
obtained and a probable functional incompatibility of this
amine with the typical reaction conditions can be suspected.17
A specific study would be required to understand the nature of
this issue, and experimental adaptations would probably be
needed to overcome this particular problem.
Attempts Using Classical Palladium-Catalyzed Reac-
tions. At this stage, we found it useful to perform a comparison
between our electrochemical process and classical cross-
coupling reactions, such as Suzuki and Stille reactions. To
this end, the cross-coupling of 4-(6-chloropyridazin-3-yl)-
morpholine 1a and either phenylboronic acids or aryltributyl-
stannanes18 was undertaken under typical conditions.19 Results
are summarized in Table 3.
It is worth noting that, under standard reaction conditions,
Suzuki coupling is less efficient than our electrochemical
process, which always gave final products in higher yields,
especially with electron-deficient aryl moieties. It can be noted
that, in all cases, this latter reaction did not go to completion
despite extended reaction times (60 h), thus revealing some
limitations of this methodology with these specific substrates,
presumably by catalyst poisoning through nitrogen coordina-
B
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ab c d
, , ,
Table 1. Cross-Coupling Reactions between 4-(6-Chloropyridazin-3-yl)morpholine 1a and Aryl or Heteroaryl Halides
a
Typical reaction conditions: iron/nickel (64/36) rod anode, nickel foam cathode, DMF (50 mL), tetrabutylammonium bromide (1.2 mmol), 1,2-
dibromoethane (2.5 mmol), NiBr2bpy complex (10 mol %), 4-(6-chloropyridazin-3-yl)morpholine 1a (4 mmol), aryl or heteroaryl halide (8 mmol),
b
c
d
I = 0.2 A. Isolated yield. One additional equivalent of aryl- or heteroaryl halide was added after 2.5 h electrolysis. Stoichiometric amounts of 4-(6-
chloropyridazin-3-yl)morpholine (4 mmol) and aryl bromide (4 mmol) were used.
tion to palladium.20 The Stille method did not provide notable
improvements in the heterocoupling process, and only
moderate yields (22−41%) were obtained, albeit more
homogeneous than in the case of Suzuki conditions.
30% GC yield. Attempts to optimize the reaction conditions
failed since the coupling process was hampered by the
formation of a significant amount of the biaryl resulting from
the homocoupling of bromoanisole. Working at lower temper-
atures, around 50 or 60 °C, only afforded traces of the desired
product 2b, and the biaryl remained the major product formed
in the reaction. The controlled dropwise addition of 4-
bromoanisole to the mixture, at 75 °C to intend to the
minimization of the homocoupling, did not allow the expected
improvement. In this case, the hydrodehalogenation product of
4-bromoanisole was the major product observed in the
reaction.
Mechanistic Aspects of the Electrochemical Cross-
Coupling. An electrochemical study of NiBr2bpy was under-
taken in the presence of 4-(6-chloropyridazin-3-yl)morpholine
1a (MPzCl). The cyclic voltammogram of NiBr2bpy (black
curve, Figure 2) exhibits two partially reversible single-electron
reduction steps corresponding to the successive formation of
nickel(I) and nickel(0) complexes. In the presence of MPzCl
(blue (1 equiv) and red (2 equiv) curves), the loss of the
reversibility of the two reduction steps of nickel(II) to nickel(0)
To further explore other classical palladium-catalyzed C−C
bond formation methods, the Negishi reaction was then
investigated starting from the model aminohalopyridazine (4-
(6-halopyridazin-3-yl)morpholine) and the organozinc species
prepared from 4-bromoanisole.21 The reaction, conducted at 50
°C in the presence of 10 mol % tetrakis(triphenylphosphine)-
palladium, or 10 mol % palladium chloride, associated with 40
mol % triphenylphosphine, was unsuccessful and led mainly to
the formation of the homocoupling product, 4,4′-dimethox-
ybiphenyl, starting from either 6-chloro or 6-iodo derivatives as
the starting pyridazine. We then tried to employ another
method described by Gosmini and co-workers,22 involving a
zinc/cobalt system in acetonitrile. Unfortunately, the reaction
of 4-bromoanisole with 4-(6-chloropyridazin-3-yl)morpholine
1a did not give the desired product in satisfactory yield. Indeed,
the best result was obtained by heating the reaction mixture at
75 °C, for which the coupling product 2b was observed in only
C
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a b c
, ,
Table 2. Cross-Couplings between 3-Amino-6-Chloropyridazines 1 and Aryl or Heteroaryl Halides
a
Typical reaction conditions: iron/nickel (64/36) rod anode, nickel foam cathode, DMF (50 mL), tetrabutylammonium bromide (1.2 mmol), 1,2-
dibromoethane (2.5 mmol), NiBr2bpy complex (10 mol %), 3-amino-6-chloropyridazine (4 mmol), aryl or heteroaryl halide (8 mmol), I = 0.2 A.
b
c
Isolated yield. One additional equivalent of aryl halide was added after 2.5 h electrolysis.
was observed, which accounts for the fast insertion of
zerovalent nickel onto the C−Cl bond of MPzCl.
From the mechanistic point of view, the first peak at −1.15
V/SCE is supposed to correspond to the initial formation of an
MPzNiIICl intermediate. Moreover, at −1.3 V/SCE, a second
peak of lower intensity is visible, which might be assigned to the
formation of an MPzNiI complex by reduction of MPzNiIICl.
To confirm the formation of this intermediate species, cyclic
voltammograms were performed at different scan rates (Figure
3). Indeed, as the MPzNiI complex was assumed to have a very
short lifetime, it was envisaged that an increase of the scan rates
would result in an increase of the intensity of the corresponding
D
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ab c
, ,
Table 3. Suzuki and Stille Cross-Couplings with 4-(6-Chloropyridazin-3-yl)morpholine 1a
a
Isolated yields obtained from typical Suzuki coupling conditions: 1,4-dioxane (3 mL), 4-(6-chloropyridazin-3-yl)morpholine 1a (1 mmol),
b
arylboronic acid (1.2 mmol), cesium carbonate (2.2 mmol), tetrakis(triphenylphosphine)palladium (5 mol %), reflux, 18−60 h. Isolated yields
obtained from typical Stille coupling conditions: toluene (8 mL), 4-(6-chloropyridazin-3-yl)morpholine 1a (1 mmol), organotin compound (1.2
mmol), tetrakis(triphenylphosphine)palladium (5 mol %), reflux, 18−48 h. For comparison, isolated yields obtained from the electrochemical
coupling.
c
Figure 3. Cyclic voltammograms at a glassy carbon electrode in DMF
+ Bu4NBr (0.1 mol·L−1) of NiBr2bpy (C = 5.10−3 mol·L−1) in the
presence of 1a (C = 10−2 mol·L−1) at different scan rates.
Figure 2. Cyclic voltammograms at a glassy carbon electrode in DMF
+ Bu4NBr (0.1 mol·L−1) of NiBr2bpy (C = 10−2 mol·L−1) in the
absence (black curve) and in the presence of MPzCl, C = 1.10−2
mol·L−1 (blue curve) and C = 2.10−2 mol·L−1 (red curve). v = 50
mV·s−1.
The monoelectronic reduction of this intermediate (step c),
followed by a second oxidative addition in the presence of the
aromatic halide, leads to an APzNiIII(Cl)Ar complex (step d).
Consequently, the latest step should correspond to the
reductive elimination of the complex (step e), giving the
desired coupling product. This event should be associated with
the release of NiIX species, which is further electrochemically
reduced to regenerate Ni0 (step f).
peak (−1.3 V/SCE). As postulated, increasing the reaction rate
from 50 to 600 mV·s−1 led to the observation of a more distinct
peak at −1.3 V/SCE, which may account for the formation of a
transient MPzNiI complex.
As we already reported in a preliminary work, the oxidative
addition of an electrogenerated zerovalent nickel complex
occurs faster on chloropyridazines than on aryl bromides.23 On
the basis of this postulate, we propose the following reaction
mechanism, taking into account the crucial role of a transient
NiI species in the catalytic process (Scheme 2).
In the putative catalytic cycle, the NiBr2bpy precatalyst is first
reduced to Ni0 (step a) (Scheme 2). Nickel(0) is then
subjected to an oxidative addition onto 3-amino-6-chloropyr-
idazine (APzCl) to give an APzNiIICl intermediate (step b).
CONCLUSION
■
In conclusion, results reported in this paper indicate that an
electrochemical method can constitute a valuable alternative to
classical reactions for the cross-coupling of aminohalopyrida-
zines and aryl bromides. Indeed, it was shown that 3-amino-6-
arylpyridazines can be obtained in good yields by nickel-
catalyzed electrochemical arylation of 3-amino-6-chloropyrida-
zines, using an iron/nickel electrode as the sacrificial anode at
E
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2−5%MeOH (50 mL) were added. After separation of the two phases,
the aqueous layer was extracted with CH2Cl2/2−5% MeOH (2 × 50
mL). The combined organic layers were dried over MgSO4, filtered,
and evaporated under vacuum. The purification of the crude by
chromatography on silica (elution with pentane/acetone (95/5), then
(90/10)) gave the desire product.
Scheme 2. Reaction Mechanism
Method C (Compounds 1j and 1k). To a solution of pyrrole or
imidazole (36.9 mmol) in DMF (40 mL) was added sodium hydride
(40.6 mmol of a 60% NaH, dispersion on mineral oil). The resulting
solution was stirred at room temperature for 5 min before being
transferred dropwise by means of a dropping funnel to a solution of
3,6-dichloropyridazine (33.6 mmol) in DMF (20 mL). The mixture
was stirred at room temperature (for pyrrole) or at 80 °C (for
imidazole). A saturated NH4Cl solution (50 mL) was added, and the
resulting solution was extracted with CH2Cl2/2−5% MeOH (3 × 50
mL). The combined organic layers were dried over MgSO4, filtered,
and evaporated under vacuum. Trituration of the crude in pentane
afforded the product as a solid.
Typical Procedure for the Cross-Coupling Reactions. To an
undivided electrochemical cell, fitted with an iron/nickel (64/36) rod
as the anode and surrounded by a nickel foam as the cathode, were
added DMF (50 mL), tetrabutylammonium bromide (1.2 mmol, 400
mg), and 1,2-dibromoethane (2.5 mmol, 215 μL). The mixture was
electrolyzed under argon at a constant current intensity of 0.2 A at
room temperature for 15 min. The current was then stopped, and the
NiBr2bpy complex (0.4 mmol, 150 mg), 3-amino-6-chloropyridazine
(4 mmol), and aromatic or heteroaromatic halides (8 mmol) were
sequentially added. The solution was electrolyzed at 0.2 A at room
temperature until one of the starting materials was totally consumed.
Typical Workup and Purification. A saturated aqueous solution
of EDTA (100 mL) was added to the mixture, and the solution was
extracted with CH2Cl2 containing 2−5% methanol (3 × 100 mL). The
combined organic layers were dried over MgSO4, filtered, and
evaporated under vacuum. The crude product was purified by flash
chromatography on silica (20−45 μM), eluted with a gradient of
solvents (pentane/acetone). For some polar cross-coupling com-
pounds, a mixture of acetone−methanol (95/5) was necessary.
4-(6-Chloropyridazin-3yl)morpholine (1a):25 Pale yellow solid.
Yield: 6.13 g (92%); mp 132.5−134.5 °C; GC (80 °C, 6 °C/min) RT
= 12.84 min; ATR-FTIR (neat, cm−1) ν 3081, 2976, 2863, 1421, 1262,
1244, 1168, 1111, 925, 834, 677; 1H NMR (400 MHz, CDCl3) δ 7.24
(d, J = 9.5 Hz, 1H), 6.90 (d, J = 9.5 Hz, 1H), 3.83 (t, J = 5.0 Hz, 4H),
3.60 (t, J = 5.0 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 159.2, 147.4,
128.8, 115.1, 66.4, 45.4; MS, m/z (relative intensity) 201 (34), 200
(38), 199 ([M].+, 100), 198 (74), 171 (28), 170 (37), 169 (13), 168
(88), 164 (19), 156 (39), 144 (28), 143 (21), 142 (80), 141 (45), 86
(15), 79 (52), 78 (15), 73 (33), 52 (21).
room temperature. Comparative experiments involving classical
reactions, such as Suzuki, Stille, or Negishi cross-couplings,
revealed that the electrochemical method constitutes an
alternative tool when the former struggle to deliver the biaryl
compound. Electrochemical analyses additionally showed that
the reaction mechanism involves the formation of a transient
NiI species, which is a widely postulated intermediate, albeit
rarely demonstrated. Current works are dedicated to the
electrochemical C−H activation of pyridazines in the presence
of nickel complexes and will be reported in due course.
EXPERIMENTAL SECTION
■
General. Solvents and reagents were purchased from commercial
suppliers and used without further purification. The nickel bromide
2,2′-bipyridine complex (NiBr2bpy) was prepared from nickel bromide
hydrate and 2,2′-bipyridyl.24 Reactions were monitored by gas
chromatography (GC) using a chromatograph fitted with a capillary
column (l = 5 m, Ø = 0.32 mm, df = 0.5 μm). Melting points were
measured on a capillary melting apparatus and are uncorrected.
Infrared spectra were recorded on an ATR-FTIR spectrophotometer.
NMR spectra were recorded in CDCl3 at 400 MHz (1H), 100 MHz
(13C), and 376 MHz (19F) on a spectrometer. Chemical shift (δ) are
reported in parts per million (ppm) relative to the residual solvent
signal. Coupling constant values (J) are given in hertz (Hz) and refer
to apparent multiplicities, indicated as follows: s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), and dd (doublet of doublets).
Mass spectra (in electronic impact (EI+) ionization mode) were
measured on a GC-MS spectrometer. High-resolution mass spectra
(HRMS) were performed on a Q-TOF mass spectrometer in positive
electrospray ionization (ESI+) mode. Purifications were performed by
flash chromatography on silica gel (granulometry 70−200 μm).
Compounds that have been previously described in the literature are
linked to the corresponding bibliographic references.
3-Chloro-6-(piperidin-1-yl)pyridazine (1b):26 Pale brown solid.
Yield: 5.10 g (77%); mp 74−76 °C; GC (80 °C, 6 °C/min) RT =
13.04 min; ATR-FTIR (neat, cm−1) ν 3050, 2927, 2854, 1660, 1582,
1
1435, 829, 761; H NMR (400 MHz, CDCl3) δ 7.18 (d, 1H, J = 9.5
Hz), 6,89 (d, 1H, J = 9.5 Hz), 3.70−3.53 (m, 4H), 1.70−1.56 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 159.1, 145.9, 128.6, 115.3, 46.3,
25.3, 24.4; MS, m/z (relative intensity) 199 (34), 198 (17), 197
([M].+, 100), 170 (14), 168 (43), 162 (42), 142 (12), 84 (77), 79
(17), 56 (21).
3-Chloro-6- (4-methylpiperazin-1-yl)pyridazine (1c):27 Dark
brown solid. Yield: 4.65 g (65%); mp 105.5−106.5 °C; GC (80 °C, 6
°C/min) RT = 14.15 min; ATR-FTIR (neat, cm−1) ν 3064, 2935,
General Procedures for the Preparation of 3-Amino-6-
chloropyridazines 1a−1k. Method A (Compounds 1a−1h). To a
round-bottom flask fitted with a condenser were added DMF (50 mL),
3,6-dichloropyridazine (33.6 mmol), the amine (36.9 mmol, 1.1
equiv), and triethylamine (50.3 mmo, 1.5 equiv). The resulting
mixture was stirred at 80 °C for 17−20 h. H2O (100 mL) was added,
and the resulting solution was extracted with CH2Cl2/2−5% MeOH
(3 × 50 mL). The combined organic layers were dried over MgSO4,
filtered, and evaporated under vacuum. Trituration of the crude in
pentane afforded the product as a solid (except for the product 1h,
where purification by chromatography on silica is required).
1
2842, 1668, 1583, 1425, 1253, 1140, 832, 771; H NMR (400 MHz,
CDCl3) δ 7.20 (d, J = 9.5 Hz, 1H), 6.90 (d, J = 9.5 Hz, 1H), 3.64 (t, J
= 5.0 Hz, 4H), 2.51 (t, J = 5.0 Hz, 4H) 2.33 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 159.1, 146.8, 128.7, 115.3, 54.5, 46.1, 45.0; MS, m/z
(relative intensity): 212 ([M].+, 6), 168 (10), 157 (12), 156 (10), 155
(32), 154 (15), 142 (31), 114 (6), 83 (43), 82 (100).
4−6-(Chloropyridazin-3-yl)piperazine-1-carbaldehyde
(1d):28 Brownish solid. Yield: 4.15 g (55%); mp 153−155 °C; GC (80
°C, 6 °C/min) RT = 20.20 min; ATR-FTIR (neat, cm−1) ν 3050,
Method B (Compound 1i). 3,6-Dichloropyridazine (33.6 mmol),
para-anisidine (33.6 mmol), and potassium carbonate were heated at
80 °C, neat in a Schlenk tube during 72 h. H2O (50 mL) and CH2Cl2/
1
2924, 2866, 1649 (νCO), 1582, 1431, 1247, 1165, 1005, 659; H
NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.28 (d, J = 9.5 Hz, 1H),
F
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6.97 (d, J = 9.5 Hz, 1H), 3.78 (t, J = 5.1 Hz, 2H), 3.70 (t, J = 5.1 Hz,
2H), 3.60 (t, J = 5.1 Hz, 2H), 3.53 (t, J = 5.1 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 160.9, 158.8, 147.7, 129.1, 115.8, 45.7, 45.0, 44.8,
39.5; MS, m/z (relative intensity) 228 (10), 226 ([M].+, 33), 225 (12),
191 (19), 168 (23), 157 (21), 156 (41), 155 (61), 154 (62), 144 (36),
142 (100), 120 (16), 79 (20), 73 (14), 68 (17).
m/z (relative intensity) 182 (5), 181 (34), 180 ([M].+, 11), 179 (100),
152 (12), 145 (5), 144 (49), 117 (18), 116 (13), 91 (14), 89 (22), 64
(9), 63 (18).
4-(6-Phenylpyridazin-3-yl)morpholine (2a): White crystals.
Yield: 600 mg (62%); mp 153−155 °C; FC: elution with a gradient
of pentane/acetone (90/10), (80/20), and (70/30); GC (80 °C, 6
°C/min) RT = 21.05 min; ATR-FTIR (neat, cm−1) ν 3057, 2972,
3-Chloro-6-(4-phenylpiperazin-1-yl)pyridazine (1e):29 Pale
brown solid. Yield: 8.28 g (90%); mp 164−166 °C (lit.: 168−169
°C); GC (80 °C, 6 °C/min) RT = 23.99 min; ATR-FTIR (neat, cm−1)
ν 3057, 2853, 1667, 1597, 1583, 1528, 1441, 1231, 1152, 939, 760; 1H
NMR (400 MHz, CDCl3) δ 7.33−7.28 (m, 2H), 7.25 (d, J = 9.5 Hz,
1H), 6.99−6.90 (m, 4H), 3.81 (t, J = 5.1 Hz, 4H), 3.33 (t, J = 5.1 Hz,
4H); 13C NMR (100 MHz, CDCl3) δ 159.1, 151.0, 147.1, 129.3,
128.9, 120.4, 116.5, 115.4, 49.0, 45.1; MS, m/z (relative intensity) 276
(7), 274 ([M].+, 19), 239 (7), 145 (12), 133 (13), 132 (100), 120
(35), 119 (5), 105 (13), 104 (81), 91 (6), 79 (6), 77 (24), 51 (5).
3-Chloro-6-(pyrrolidin-1-yl)pyridazine (1f):30 Pale brown solid.
Yield: 4.97 g (81%); mp 126−128 °C; GC (80 °C, 6 °C/min) RT =
12.47 min; ATR-FTIR (neat, cm−1) ν 3048, 2957, 2864, 2360, 1672,
1
2865, 1424, 1262, 1110, 926, 747, 700, 638; H NMR (400 MHz) δ
8.00 (d, J = 7.2 Hz, 2H), 7.66 (d, J = 9.5 Hz, 1H), 7.47 (t, J = 7.2 Hz,
2H), 7.41 (d, J = 7.2 Hz, 1H), 6.95 (d, J = 9.5 Hz, 1H), 3.86 (t, J = 4.7
Hz, 4H), 3.67 (t, J = 4.7 Hz, 4H); 13C NMR (100 MHz) δ 159.0,
151.6, 136.7, 128.8, 126.2, 126.0, 125.2, 112.8, 66.6, 45.4; MS, m/z
(relative intensity) 242 (15), 241 ([M]+, 100), 240 (72), 213 (20),
212 (7), 211 (22), 210 (98), 199 (6), 198 (27), 197 (6), 196 (29), 185
(10), 184 (77), 183 (63), 157 (6), 156 (12), 155 (11), 115 (40), 104
(8), 77 (7); HRMS (ESI+) m/z calcd for C14H16N3O [M + H],
242.128789; found, 242.1289149.
4-[6-(4-Methoxyphenyl)pyridazin-3-yl]morpholine (2b):34
Pale yellow crystals. Yield: 495 mg (46%); mp 174−176 °C; FC:
elution with a gradient of pentane/acetone (90/10), (80/20), and
(70/30); GC (80 °C, 6 °C/min) RT = 24.62 min; ATR-FTIR (neat,
cm−1) ν 2964, 2856, 1440, 1280, 1234, 1112, 1024, 931, 817, 604; 1H
NMR (400 MHz) δ 7.93 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 9.5 Hz, 1H),
6.97 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.6 Hz, 1H), 3.89−3.82 (m, 7H),
3.63 (t, J = 4.5 Hz, 4H); 13C NMR (100 MHz) δ 160.4, 158.8, 151.4,
129.2, 127.2, 124.8, 114.2, 113.1, 66.6, 55.3, 45.5; MS, m/z (relative
intensity) 272 (17), 271 ([M].+, 100), 270 (57), 243 (12), 241 (16),
240 (64), 228 (14), 226 (22), 215 (7), 214 (54), 213 (49), 186 (5),
185 (7), 171 (7), 145 (15), 132 (7), 115 (5); HRMS (ESI+) m/z calcd
for C15H18N3O2 [M + H], 272.139353; found, 272.139745.
1
1590, 1527, 1470, 1453, 1159, 833; H NMR (400 MHz, CDCl3) δ
7.13 (d, J = 9.5 Hz, 1H), 6.61 (d, J = 9.5 Hz, 1H), 3.49 (t, J = 6.4 Hz,
4H), 2.03 (t, 4H, J = 6.4 Hz); 13C NMR (100 MHz, CDCl3) δ 156.8,
145.1, 128.4, 114.8, 46.9, 25.4; MS, m/z (relative intensity) 185 (35),
184 (16), 183 ([M].+, 100), 157 (11), 156 (34), 155 (28), 154 (84),
128 (14), 79 (13), 70 (33).
6-Chloro-N,N-diethylpyridazin-3amine (1g):31 Pale yellow
solid. Yield: 5.03 g (81%); mp 52.5−53.5 °C; GC (80 °C, 6 °C/
min) RT = 7.15 min; ATR-FTIR (neat, cm−1) ν 3063, 2975, 2932,
2870, 2360, 2341, 1673, 1582, 1524, 1489, 1446, 1425, 1200, 1167,
1
834, 755; H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 9.5 Hz, 1H),
6.71 (d, J = 9.5 Hz, 1H), 3.56 (q, J = 7.0 Hz, 4H), 1.19 (t, J = 7.0 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 157.2, 145.0, 128.4, 113.8, 43.0,
12.6; MS, m/z (relative intensity) 187 (29), 186 (25), 185 ([M].+, 79),
184 (31), 170 (20), 158 (31), 156 (100), 144 (14), 142 (41), 79 (18).
N,N-Diallyl-6-chloropyridazin-3-amine (1h):31 Yellow-orange
oil. Yield: 4.56 g (65%); GC (80 °C, 6 °C/min) RT = 11.77 min;
ATR-FTIR (neat, cm−1) ν 3083, 2982, 2915, 1642, 1586 (νCC),
1476, 1414, 1166, 921; 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 9.5
Hz, 1H), 6.70 (d, J = 9.5 Hz, 1H), 5.90−5.81 (m, 2H), 5.19 (d, J = 1.5
Hz, 2H), 5.16 (dd, J = 1.2, J = 8.5 Hz, 2H), 4.16 (d, J = 5.2 Hz, 4H);
13C NMR (100 MHz, CDCl3) δ 158.0, 146.0, 132.6, 130.3, 114.6,
117.0, 50.6; MS, m/z (relative intensity) 210 (10), 208 (26), 194 (10),
174 (21), 170 (31), 169 (31), 168 (100), 167 (13), 166 (33), 157
(13), 156 (13), 155 (32), 154 (36), 141 (10), 133 (25), 132 (13), 105
(27), 79 (16), 73 (13), 54 (8).
4-[6-(3-Tolyl)pyridazin-3-yl]morpholine (2c): Pale yellow
crystals. Yield: 650 mg (64%); mp 153−154.5 °C; FC: elution with
pentane/acetone (80/20); GC (80 °C, 6 °C/min) RT = 22.45 min;
ATR-FTIR (neat, cm−1) ν 2972, 2915, 2863, 1594, 1440, 1379, 1111,
1
929, 793; H NMR (400 MHz) δ 7.87 (s, 1H), 7.75 (d, J = 7.4 Hz,
1H), 7.65 (d, J = 9.5 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.22 (d, J = 7.4
Hz, 1H), 6.95 (d, J = 9.5 Hz, 1H), 3.86 (t, J = 4.7 Hz, 4H), 3.67 (t, J =
4.5 Hz, 4H), 2.43 (s, 3H); 13C NMR (100 MHz) δ 159.0, 151.7 138.5,
136.5, 129.6, 128.7, 126.7, 125.3, 123.0, 112.8, 66.6, 45.4, 21.5; MS, m/
z (relative intensity) 256 (16), 255 ([M] .+, 100), 254 (75), 228 (5),
227 (17), 226 (6), 225 (23), 224 (95), 213 (6), 212 (26), 211 (6), 210
(26), 199 (11), 198 (77), 197 (65), 196 (6), 171 (5), 170 (9), 169 (9),
129 (21), 128 (12), 127 (7), 118 (8), 115 (10), 91 (8); HRMS (ESI+)
m/z calcd for C15H18N3O [M + H], 256.144439; found, 256.144849.
4-[6-(4-Fluorophenyl)pyridazin-3-yl]morpholine (2d): Pale
yellow crystals. Yield: 605 mg (58%); mp 166−167.5 °C; FC: elution
with a gradient of pentane/acetone (90/10), (80/20), (70/30), and
(50/50); GC (80 °C, 6 °C/min) RT = 20.93 min; ATR-FTIR (neat,
6-Chloro-N-(4-methoxyphenyl)pyridazin-3-amine (1i):32
Brown solid. Yield: 4.34 g (55%); mp 158−159 °C (lit.: 145−147
°C); GC (80 °C, 6 °C/min) RT = 19.21 min; ATR-FTIR (neat, cm−1)
ν 3230, 3036, 2962, 1508, 1444, 1243, 1035, 840, 819; 1H NMR (400
MHz, CDCl3) δ 7.43 (broad s, 1H), 7.28−7.18 (m, 3H), 6.94 (m,
3H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.4, 157.3,
147.5, 131.3, 129.4, 124.9, 115.7, 114.9, 55.6; MS, m/z (relative
intensity) 237 (18), 236 (40), 235 ([M].+, 56), 234 (100), 222 (7),
221 (5), 220 (19), 219 (9), 185 (9).
1
cm−1) ν 3055, 2972, 2867, 1434, 1227, 1111, 927, 831, 822, 601; H
NMR (400 MHz) δ 7.97 (broad t, J = 6.2 Hz, 2H), 7.61 (d, J = 9.2 Hz,
1H), 7.14 (dd, J = 7.3, J = 8.5 Hz, 2H), 6.95 (d, J = 9.2 Hz, 1H), 3.92−
3.83 (m, 4H), 3.71−3.63 (m, 4H); 13C NMR (100 MHz) δ 163.4 (d,
J1
= 248.4 Hz), 159.0, 150.7, 132.8 (d, J4
= 3.1 Hz), 127.8 (d,
C−F
J3C−F = 8.3 Hz), 124.9, 115.7 (d, J2
= 21.7 Hz), 112.9, 66.5, 45.4;
C−F
C−F
3-Chloro-6-(1H-pyrrol-1-yl)pyridazine (1j):33 Brown solid.
Yield: 4.99 g (83%); mp 179−180 °C (lit.: 180−182 °C); GC (80
°C, 6 °C/min) RT = 9.45 min; ATR-FTIR (neat, cm−1) ν 3136, 3042,
19F NMR (376 MHz) δ −113.2; MS, m/z (relative intensity) 260
(13), 259 ([M]+, 100), 258 (79), 231 (16), 230 (6), 229 (18), 228
(97), 217 (5), 216 (27), 215 (8), 214 (29), 203 (12), 202 (71), 201
(56), 200 (5), 188 (5), 175 (6), 174 (10), 173 (12), 147 (6), 133 (37),
122 (8), 52 (5); HRMS (ESI+) m/z calcd for C14H15FN3O [M + H],
260.1199367; found, 260.119747.
1
1477, 1430, 1368, 1327, 1165, 914, 834, 731; H NMR (400 MHz,
CDCl3) δ 7.58−7.56 (m, 3H), 7.51 (d, J = 9.2 Hz, 1H), 6.46−6.44 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 153.2, 153.0, 130.2, 118.4,
118.3, 113.1; MS, m/z (relative intensity) 182 (5), 181 (34), 180 (11),
179 ([M].+, 100), 152 (12), 145 (5), 144 (49), 117 (18), 116 (13), 91
(14), 89 (22), 64 (9), 63 (18).
4-[6-(3-(Trifluoromethyl)phenyl)pyridazin-3-yl]morpholine
(2e): Pale yellow solid. Yield: 865 mg (70%); mp 116−117.5 °C; FC:
elution with a gradient of pentane/acetone (90/10) and (80/20); GC
(80 °C, 6 °C/min) RT = 20.67 min; ATR-FTIR (neat, cm−1) ν 2969,
3-Chloro-6-(1H-imidazol-1-yl)pyridazine (1k):33 Yellowish
solid. Yield: 4.41 g (73%); mp 180−182 °C (lit.: 178−180 °C); GC
(80 °C, 6 °C/min) RT = 9.85 mi; ATR-FTIR (neat, cm−1) ν 3155,
1
2862, 1416, 1338, 1263, 1179, 1111, 1073, 929, 812, 706; H NMR
(400 MHz) δ 8.29 (s, 1H), 8.17 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 9.5
Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 6.98 (d, J =
9.5 Hz, 1H), 3.86 (t, J = 4.0 Hz, 4H), 3.70 (t, J = 4.0 Hz, 4H); 13C
1
3041, 1660, 1481, 1433, 1309, 1158, 1034, 819, 743, 650; H NMR
(400 MHz, CDCl3) δ 8.48 (s, 1H), 7.76−7.5 (m, 1H), 7.70 (d, J = 9.2
Hz, 1H), 7.65 (d, J = 9.2 Hz, 1H), 7.29 (broad s, 1H); 13C NMR (100
MHz, CDCl3) δ 155.1, 151.3, 135.0, 131.7, 130.9, 119.4, 116.2; MS,
NMR (100 MHz) δ 159.2, 150.0, 137.4, 131.3 (q, J2
= 32.4 Hz),
C−F
129.3, 128.9, 125.3 (q, J3C−F = 3.7 Hz), 125.0, 124.1 (q, J1C−F = 272.5
G
dx.doi.org/10.1021/jo3022428 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Hz), 122.7 (q, J3C−F = 4.0 Hz), 112.6, 66.5, 45.3; 19F NMR (376 MHz)
δ −62.7; MS, m/z (relative intensity) 310 (18), 309 ([M]+, 100), 308
(79), 290 (18), 281 (15), 280 (5), 279 (23), 278 (92), 267 (6), 266
(27), 265 (6), 264 (25), 253 (14), 252 (81), 251 (50), 238 (6), 224
(8), 223 (9), 184 (7), 183 (31), 172 (8), 145 (6), 133 (6); HRMS
(ESI+) m/z calcd for C15H15F3N3O [M + H], 310.116173; found,
310.116459.
(d, J = 9.5 Hz, 1H), 7.41−7.39 (m, 1H), 6.99 (d, J = 9.5 Hz, 1H), 3.86
(t, J = 4.8 Hz, 4H), 3.68 (t, J = 4.8 Hz, 4H); 13C NMR (100 MHz) δ
159.2, 149.7, 149.0, 147.1, 133.3, 132.4, 125.0, 123.8, 112.7, 66.5, 45.2;
MS, m/z (relative intensity) 243 (16), 242 ([M]+, 100), 241 (85), 214
(23), 213 (7), 212 (21), 211 (100), 200 (6), 199 (33), 197 (23), 186
(9), 185 (68), 184 (63), 116 (29), 105 (9), 104 (6), 89 (9), 79 (9), 78
(6), 52 (6); HRMS (ESI+) m/z calcd for C13H15N4O [M + H],
243.124038; found, 243.124133.
Ethyl 4-(6-Morpholinopyridazin-3-yl)benzoate (2f): Pale
brown solid. Yield: 720 mg (58%); mp 187−188 °C; FC: elution
with a gradient of pentane/acetone (95/5) until 100% acetone; GC
(80 °C, 6 °C/min) RT = 27.35 min; ATR-FTIR (neat, cm−1) ν 2973,
4-[6-(Quinolin-2-yl)pyridazin-3-yl]morpholine (2k): Pale
brown solid. Yield: 303 mg (26%); mp 231−233 °C; FC: elution
with a gradient of pentane/acetone (90/10), then (80/20); GC (80
°C, 6 °C/min) RT = 27.14 min; ATR-FTIR (neat, cm−1) ν 2956,
1
2868, 1702, 1434, 1266, 1117, 827, 755; H NMR (400 MHz) δ 8.15
1
(d, J = 8.5 Hz, 2H), 8.09 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 9.6 Hz, 1H),
7.00 (d, J = 9.6 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 3.88 (t, J = 4.8 Hz,
4H), 3.72 (t, J = 4.8 Hz, 4H), 1.42 (t, J = 7.1 Hz, 3H); 13C NMR (100
MHz) δ 163.9, 156.6, 148.0, 138.1, 128.1, 127.7, 123.3, 123.1, 110.2,
64.1, 58.6, 42.8, 11.9; MS, m/z (relative intensity) 314 (14), 313
([M]+, 75), 312 (73), 285 (13), 284 (19), 283 (26), 282 (100), 271
(7), 270 (36), 269 (8), 268 (30), 257 (13), 256 (72), 255 (63), 254
(25), 240 (12), 228 (23), 227 (6), 183 (6), 159 (8); HRMS (ESI+) m/
z calcd for C17H20N3O3 [M + H], 314.149918; found, 314.150115.
Ethyl 3-(6-Morpholinopyridazin-3-yl)benzoate (2g): Pale
yellow solid. Yield: 875 mg (70%); mp 98−99 °C; FC: elution with
a gradient of pentane/acetone (95/5) and (90/10); GC (80 °C, 6 °C/
min) RT = 27.18 min; ATR-FTIR (neat, cm−1) ν 2969, 2868, 1713
(νCO), 1444, 1241, 1109, 1083, 929, 749, 669; 1H NMR (400 MHz)
δ 8.61 (s, 1H), 8.26 (d, J = 7.7 Hz, 1H), 8.08 (d, J = 7.7 Hz, 1H), 7.73
(d, J = 9.5 Hz, 1H), 7.54 (t, J = 7.7 Hz, 1H), 6.98 (d, J = 9.5 Hz, 1H),
4.40 (q, J = 7.1 Hz, 2H), 3.86 (t, J = 4.8 Hz, 4H), 3.68 (t, J = 4.8 Hz,
4H), 1.40 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz) δ 166.4, 159.1,
150.6, 136.9, 131.1, 130.2, 129.8, 129.0, 126.9, 125.3, 112.8, 66.5, 61.2,
45.3, 14.4; MS, m/z (relative intensity) 314 (15), 313 ([M]+, 92), 312
(80), 285 (16), 284 (22), 283 (26), 282 (100), 271 (8), 270 (34), 269
(10), 268 (35), 257 (14), 256 (69), 255 (58), 254 (27), 240 (15), 228
(20), 227 (8), 182 (9), 159 (11); HRMS (ESI+) m/z calcd for
C17H20N3O3 [M + H], 314.149918; found, 314.150295.
Ethyl 2-(6-Morpholinopyridazin-3-yl)benzoate (2h): White
solid. Yield: 380 mg (30%); mp 124−126 °C; FC: elution with
pentane/acetone (80/20); GC (80 °C, 6 °C/min) RT = 24.43 min;
ATR-FTIR (neat, cm−1) ν 2975, 2840, 1720, 1432, 1285, 1115, 930,
754; 1H NMR (400 MHz) δ 7.93 (d, J = 7.8 Hz, 1H), 7.62−7.57 (m,
2H), 7.51−7.47 (m, 1H), 7.38 (d, J = 9.4 Hz, 1H), 6.94 (d, J = 9.4 Hz,
1H), 4.22 (q, J = 7.1 Hz, 2H), 3.88 (t, J = 5.1 Hz, 4H), 3.68 (t, J = 5.1
Hz, 4H), 1.19 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz) δ 167.9,
158.8, 153.3, 138.7, 131.5, 130.8, 130.3, 130.2, 128.4, 128.3, 111.6,
66.6, 61.1, 45.3, 14.0; MS, m/z (relative intensity) 313 ([M]+, 48), 312
(56), 284 (20), 283 (23), 282 (100), 270 (23), 269 (9), 268 (17), 257
(10), 256 (33), 255 (20), 254 (19), 240 (10), 212 (7), 211 (18), 210
(32), 209 (8), 185 (10), 184 (15); HRMS (ESI+) m/z calcd for
C17H20N3O3 [M + H], 314.149918; found, 314.150272.
2849, 1585, 1429, 1237, 1117, 1114, 929, 826, 752; H NMR (400
MHz) δ 8.72 (d, J = 8.7 Hz, 1H), 8.66 (d, J = 9.6 Hz, 1H), 8.28 (d, J =
8.7 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.74 (t,
J = 8.2 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 9.6 Hz, 1H), 3.90
(t, J = 4.8 Hz, 4H), 3.77 (t, J = 4.8 Hz, 4H); 13C NMR (100 MHz) δ
159.8, 154.2, 151.3, 147.8, 136.9, 129.7, 129.5, 128.3, 127.8, 126.7,
118.3, 112.7, 66.6, 45.3; MS, m/z (relative intensity) 293 (14), 292
([M]+, 84), 291 (86), 281 (22), 264 (13), 263 (21), 262 (38), 261
(100), 249 (28), 247 (31), 235 (69), 234 (51), 210 (11), 209 (23),
208 (35), 207 (77), 206 (20), 192 (21), 129 (14), 128 (16); HRMS
(ESI+) m/z calcd for C17H17N4O [M + H], 293.139688; found,
293.139953.
3-(4-Methylpiperazin-1-yl)-6-[3-(trifluoromethyl)phenyl]-
pyridazine (2l): Pale yellow solid. Yield: 850 mg (66%); mp 112−114
°C; FC: elution with a gradient of pentane/acetone (80/20) until
100% acetone, then acetone/methanol (80/20); GC (80 °C, 6 °C/
min) RT = 21.45 min; ATR-FTIR (neat, cm−1) ν 2956, 2936, 2874,
1589, 1417, 1336, 1165, 1106, 1073, 810, 704; 1H NMR (400 MHz) δ
8.29 (s, 1H), 8.18 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 9.6 Hz, 1H), 7.64
(d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 9.6 Hz, 1H),
3.77 (t, J = 5.0 Hz, 4H), 3.77 (t, J = 5.0 Hz, 4H), 2.37 (s, 3H); 13C
NMR (100 MHz) δ 159.0, 149.5, 137.5, 131.3 (q, J2
= 32.4 Hz),
C−F
129.3, 128.9, 125.2 (q, J3C−F = 3.6 Hz), 125.0, 124.2 (q, J1C−F = 272.5
Hz), 122.6 (q, J3C−F = 3.9 Hz), 112.7, 54.6, 46.2, 44.9; 19F NMR (376
MHz) δ −62.7; MS, m/z (relative intensity) 322 ([M]+, 7), 278 (8),
266 (6), 265 (33), 264 (17), 253 (16), 252 (100), 223 (10), 207 (8),
183 (17), 145 (5); HRMS (ESI+) m/z calcd for C16H18F3N4 [M + H],
323.147808; found, 323.148424.
N,N-Diethyl-6-[3-(trifluoromethyl)phenyl]pyridazin-3-amine
(2m): Pale yellow oil. Yield: 805 mg (68%); FC: elution with a
gradient of pentane/acetone (95/5) then (90/10); GC (80 °C, 6 °C/
min) RT = 17.58 min; ATR-FTIR (neat, cm−1) ν 2974, 2933, 1590,
1427, 1332, 1282, 1162, 1120, 1095, 802, 698; 1H NMR (400 MHz) δ
8.23 (s, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 9.6 Hz, 1H), 7.53
(d, J = 7.6 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 6.73 (d, J = 9.6 Hz, 1H),
3.57 (q, J = 7.0 Hz, 4H), 1.18 (t, J = 7.0 Hz, 6H); 13C NMR (100
MHz) δ 157.2, 147.9, 137.9, 131.2 (q, J2C−F = 31.8 Hz), 129.2, 128.5,
124.8 (q, J3C−F = 4.2 Hz), 124.7, 124.3 (q, J1C−F = 272.4 Hz), 122.4 (q,
J3C−F = 3.9 Hz), 111.3, 43.0, 12.8; 19F NMR (376 MHz) δ −62.7; MS,
m/z (relative intensity) 296 (10), 295 ([M]+, 61), 294 (14), 280 (11),
276 (6), 267 (15), 266 (100), 253 (6), 252 (37), 240 (7), 239 (6), 183
(11); HRMS (ESI+) m/z calcd for C15H17F3N3 [M + H], 296.136909;
found, 296.137419.
4-[6-Thiophen-3-yl]pyridazin-3-yl)morpholine (2i): Pale yel-
low solid. Yield: 705 mg (71%); mp 183−185 °C; FC: elution with a
gradient of pentane/acetone (95/5), (90/10), (80/20), and (50/50);
GC (80 °C, 6 °C/min) RT = 21.33 min; ATR-FTIR (neat, cm−1) ν
1
3084, 2976, 2862, 1434, 1263, 1240, 1114, 929, 817, 798, 654; H
NMR (400 MHz) δ 7.80 (m, 2H), 7.57 (dd, J = 2.8, J = 8.9 Hz, 1H),
7.42−7.40 (m, 1H), 6.93 (dd, J = 2.8, 8.9 Hz, 1H), 3.86 (t, J = 4.7 Hz,
4H), 3.58 (t, J = 4.7 Hz, 4H); 13C NMR (100 MHz) δ 158.7, 148.5,
139.1, 126.5, 125.8, 125.3, 122.0, 113.0, 66.6, 45.4; MS, m/z (relative
intensity) 249 (7), 248 (19), 247 ([M]+, 100), 246 (74), 219 (19), 218
(10), 217 (15), 216 (78), 204 (21), 203 (5), 202 (26), 191 (11), 190
(62), 189 (63), 163 (6), 162 (10), 161 (10), 135 (7), 121 (21), 110
(6); HRMS (ESI+) m/z calcd for C12H14N3OS [M + H], 248.085210;
found, 248.085514.
3-(Pyrrolidin-1-yl)-6-[3-(trifluoromethyl)phenyl]pyridazine
(2n): White solid. Yield: 780 mg (67%); mp 130−132 °C; FC: elution
with a gradient of pentane/acetone (95/5), then (90/10); GC (80 °C,
6 °C/min) RT = 20.16 min; ATR-FTIR (neat, cm−1) ν 2961, 2864,
1
1430, 1333, 1157, 1114, 1071, 810; H NMR (400 MHz) δ 8.30 (s,
1H), 8.20 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 9.5 Hz, 1H), 7.63 (d, J = 7.6
Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 6.72 (d, J = 9.5 Hz, 1H), 3.62 (broad
s, 4H), 2.11−2.08 (m, 4H); 13C NMR (100 MHz) δ 156.7, 148.0,
138.0, 131.2 (q, J2
= 32.3 Hz), 129.2, 128.6, 124.7 (q, J3
= 3.7
C−F
C−F
Hz), 124.6, 124.3 (q, J1
= 272.4 Hz), 122.3 (q, J3
= 3.8 Hz),
4-[6-(Pyridin-3-yl)pyridazin-3-yl]morpholine (2j): Brown solid.
Yield: 300 mg (31%); mp 131−133 °C; FC: elution with a gradient of
pentane/acetone (90/10), then (80/20) and (50/50); GC (80 °C, 6
°C/min) RT = 21.53 min; ATR-FTIR (neat, cm−1) ν 2967, 2855,
C−F
C−F
112.3, 46.7, 25.4; 19F NMR (376 MHz) δ −62.7; MS, m/z (relative
intensity) 294 (18), 293 ([M] .+, 100), 292 (5), 275 (16), 274 (9), 266
(10), 265 (51), 264 (99), 251 (8), 239 (5), 238 (28), 224 (25), 204
(7), 183 (12), 172 (6), 95 (5); HRMS (ESI+) m/z calcd for
C15H15F3N3 [M + H], 294.121259; found, 294.121590.
1
1588, 1438, 1263, 1230, 1115, 926, 805, 707; H NMR (400 MHz) δ
9.14 (broad s, 1H), 8.63 (broad s, 1H), 8.36 (d, J = 7.8 Hz, 1H), 7.69
H
dx.doi.org/10.1021/jo3022428 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
6-(3-Chlorophenyl)-N,N-diethylpyridazin-3-amine (2o): Col-
orless oil. Yield: 505 mg (48%); FC: elution with a gradient of
pentane/acetone (95/5), then (90/10); GC (80 °C, 6 °C/min) RT =
20.12 min; ATR-FTIR (neat, cm−1) ν 2971, 2930, 1590, 1542, 1447,
1432, 1185, 1013, 787, 731; 1H NMR (400 MHz) δ 8.00 (s, 1H), 7.82
(d, J = 7.4 Hz, 1H), 7.51 (d, J = 9.6 Hz, 1H), 7.35−7.28 (m, 2H), 6.75
(d, J = 9.6 Hz, 1H), 3.60 (q, J = 7.0 Hz, 4H), 1.22 (t, J = 7.0 Hz, 6H);
13C NMR (100 MHz) δ 157.1, 147.9, 138.9, 134.8, 129.9, 128.1, 125.6,
124.8, 123.5, 111.3, 42.9, 12.8; MS, m/z (relative intensity) 263 (16),
262 ([M]+, 13), 261 (50), 260 (17), 246 (8), 235 (7), 234 (34), 232
(100), 221 (5), 220 (15), 219 (19), 218 (29), 207 (5), 206 (7), 149
(8), 115 (6); HRMS (ESI+) m/z calcd for C14H17ClN3 [M + H],
262.110552; found, 262.110841.
4-[6-(Diethylamino)pyridazin-3-yl]benzonitrile (2p): Pale yel-
low solid. Yield: 380 mg (38%); mp 123−125 °C; FC: elution with a
gradient of pentane/acetone (90/10), then (80/20); GC (80 °C, 6
°C/min) RT = 21.73 min; ATR-FTIR (neat, cm−1) ν 2978, 2934,
2222, 1586, 1429, 1282, 1095, 1009, 818; 1H NMR (400 MHz) δ 8.11
(d, J = 8.3 Hz, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 9.6 Hz, 1H),
6.82 (d, J = 9.6 Hz, 1H), 3.66 (q, J = 7.0 Hz, 4H), 1.25 (t, J = 7.0 Hz,
6H); 13C NMR (100 MHz) δ 157.2, 147.3, 141.3, 132.5, 125.8, 124.9,
119.0, 111.5, 111.1, 43.0, 12.8; MS, m/z (relative intensity) 254 (11),
253 (57), 252 ([M]+, 16), 238 (12), 225 (17), 224 (100), 211 (6), 210
(36), 198 (8), 197 (5), 141 (9); HRMS (ESI+) m/z calcd for
C15H17N4 [M + H], 253.144773; found, 253.144993.
(d, J = 9.6 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H),
6.97 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 9.6 Hz, 1H), 3.83 (s, 3H), 3.72 (t,
J = 4.9 Hz, 4H), 2.55 (t, J = 5.0 Hz, 4H), 2.35 (s, 3H); 13C NMR (100
MHz) δ 158.5, 156.8, 150.5, 130.5, 129.9, 129.5, 126.4, 121.2, 111.5,
111.2, 55.5, 54.7, 46.2, 44.9; MS, m/z (relative intensity) 284 ([M]+,
3), 228 (6), 227 (19), 226 (9), 215 (16), 214 (100), 203 (5), 202
(38), 199 (12), 198 (7), 185 (5), 158 (6); HRMS (ESI+) m/z calcd for
C16H21N4O [M + H], 285.170988; found, 285.171290.
3-(4-Phenylpiperazin-1-yl)-6-(para-tolyl)pyridazine (2u):
Brown solid. Yield: 950 mg (72%); mp 226−228 °C; FC: elution
with a gradient of pentane/acetone (50/50) until 100% acetone, then
actone/methanol (90/10); GC (120 °C, 8 °C/min) RT = 22.12 min;
ATR-FTIR (neat, cm−1) ν 2842, 1594, 1436, 1233, 1164, 943, 819,
752, 686; 1H NMR (400 MHz) δ 7.93 (d, J = 8.2 Hz, 2H), 7.69 (d, J =
9.6 Hz, 1H), 7.35−7.30 (m, 3H), 7.06 (d, J = 9.6 Hz, 1H), 7.02 (d, J =
8.5 Hz, 2H), 6.93 (t, J = 7.3 Hz, 1H), 3.89 (t, J = 5.5 Hz, 4H), 3.37 (t,
J = 5.5 Hz, 4H), 2.43 (s, 3H); 13C NMR (100 MHz) δ 158.7, 151.4,
151.1, 138.8, 133.8, 129.6, 129.2, 125.6, 125.2, 120.4, 116.5, 113.3,
49.2, 45.2, 21.2; MS, m/z (relative intensity) 330 ([M]+, 13), 282 (8),
281 (25), 267 (8), 265 (9), 225 (13), 212 (19), 211 (29), 210 (22),
209 (30), 208 (24), 207 (99), 199 (14), 198 (100), 191 (17), 133
(15), 132 (24), 104 (14), 91 (8), 77 (8); HRMS (ESI+) m/z calcd for
C21H23N4 [M + H], 331.191723; found, 331.191885.
1-[4-(6-Pyrrolidin-1-yl)pyridazin-3-yl)phenyl]ethanone (2v):
Pale yellow solid. Yield: 620 mg (58%); mp 176−178 °C; FC: elution
with a gradient of pentane/acetone (90/10), then (80/20) and (50/
50); GC (80 °C, 6 °C/min) RT = 26.21 min; ATR-FTIR (neat, cm−1)
3-[6-(Diethylamino)pyridazin-3-yl]benzonitrile (2q): Brown
oil. Yield: 660 mg (65%); FC: elution with a gradient of pentane/
acetone (90/10), then (80/20); GC (80 °C, 6 °C/min) RT = 21.36
min; ATR-FTIR (neat, cm−1) ν 2974, 2931, 2228, 1592, 1544, 1449,
1
ν 2972, 2873, 1680, 1596, 1546, 1457, 1404, 1263, 1177, 821; H
NMR (400 MHz) δ 8.12 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H),
7.68 (d, J = 9.4 Hz, 1H), 6.72 (d, J = 9.4 Hz, 1H), 3.63 (broad s, 4H),
2.65 (s, 3H), 2.11−2.08 (m, 4H); 13C NMR (100 MHz) δ 197.8,
156.8, 148.3, 141.6, 136.5, 128.9, 125.5, 125.0, 112.1, 46.8, 26.7, 25.5;
MS, m/z (relative intensity) 268 (19), 267 ([M]+, 100), 266 (5), 250
(7), 249 (14), 240 (10), 239 (44), 238 (85), 225 (9), 213 (6), 212
(33), 198 (16), 183 (6), 157 (5), 120 (9), 111 (9), 94 (5); HRMS
(ESI+) m/z calcd for C16H18N3O [M + H], 268.144439; found,
268.144676.
1
1282, 1185, 1015, 799, 687; H NMR (400 MHz) δ 8.28−8.26 (m,
2H), 7.64 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 9.6 Hz, 1H), 7.55 (d, J = 8.0
Hz, 1H), 6.84 (d, J = 9.6 Hz, 1H), 3.66 (q, J = 7.1 Hz, 4H), 1.26 (t, J =
7.1 Hz, 6H); 13C NMR (100 MHz) δ 157.3, 147.1, 138.3, 131.5, 129.6,
129.5, 129.0, 124.6, 118.9, 112.9, 111.3, 43.0, 12.8; MS, m/z (relative
intensity) 253 (9), 252 ([M]+, 53), 251 (16), 237 (12), 224 (16), 223
(100), 210 (6), 209 (36), 208 (5), 197 (9), 196 (5), 140 (12); HRMS
(ESI+) m/z calcd for C15H17N4 [M + H], 253.144773; found,
253.145038.
N-(4-Methoxyphenyl)-6-phenylpyridazin-3-amine (2w): Or-
ange solid. Yield: 580 mg (52%); mp 181−183 °C; FC: elution with a
gradient of pentane/acetone (90/10), then (80/20) and (70/30); GC
(100 °C, 10 °C/min) RT = 14.89 min; ATR-FTIR (neat, cm−1) ν
Ethyl 4-[6-(Diethylamino)pyridazin-3-yl]benzoate (2r): Pale
yellow oil. Yield: 720 mg (60%); FC: elution with a gradient of
pentane/acetone (95/5), then (90/10); GC (80 °C, 6 °C/min) RT =
24.44 min; ATR-FTIR (neat, cm−1) ν 2977, 2935, 1710, 1592, 1267,
1
2928, 2833, 1602, 1508, 1453, 1242, 1029, 823, 689; H NMR (400
1
MHz) δ 7.98 (d, J = 7.2 Hz, 2H), 7.62 (d, J = 9.4 Hz, 1H), 7.51 (broad
s, 1H), 7.48 (t, J = 7.0 Hz, 2H), 7.44−7.42 (m, 1H), 7.34 (d, J = 8.9
Hz, 2H), 7.04 (d, J = 9.4 Hz, 1H), 6.93 (d, J = 8.9 Hz, 2H), 3.83 (s,
3H);13C NMR (100 MHz) δ 159.9, 156.8, 152.4, 136.8, 132.0, 128.9,
128.8, 126.0, 125.7, 124.3, 114.8, 113.4, 55.6; MS, m/z (relative
intensity) 278 (12), 277 ([M]+, 62), 276 (100), 262 (18), 261 (10),
132 (5); HRMS (ESI+) m/z calcd for C17H16N3O [M + H],
278.128789; found, 278.144676.
1172, 1103, 1018, 753; H NMR (400 MHz) δ 8.13 (d, J = 8.6 Hz,
2H), 8.08 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 9.6 Hz, 1H), 6.82 (d, J = 9.6
Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.66 (q, J = 7.0 Hz, 4H), 1.42 (t, J =
7.1 Hz, 3H), 1.27 (t, J = 7.0 Hz, 6H); 13C NMR (100 MHz) δ 165.3,
155.8, 147.0, 139.9, 128.8, 128.7, 124.0, 123.9, 110.0, 59.7, 41.8, 13.1,
11.6; MS, m/z (relative intensity) 300 (10), 299 ([M]+, 53), 298 (16),
284 (7), 271 (20), 270 (100), 257 (11), 256 (53), 255 (8), 254 (7),
243 (8), 242 (35), 228 (6); HRMS (ESI+) m/z calcd for C17H22N3O2
[M + H], 300.170653; found, 300.171043.
Methyl 3-[6-(1H-pyrrol-1-yl)pyridazin-3-yl]benzoate (2x):
Yellow solid. Yield: 405 mg (36%); mp 150−152 °C; FC: elution
with a gradient of pentane/diethyl ether (90/10), then (80/20) and
pentane/acetone (90/10); GC (100 °C, 10 °C/min) RT = 23.90 min;
ATR-FTIR (neat, cm−1) ν 3119, 2959, 1722, 1486, 1431, 1293, 1256,
N,N-Diethyl-6-(3-methoxyphenyl)pyridazin-3-amine (2s):
Pale yellow oil. Yield: 450 mg (44%); FC: elution with a gradient of
pentane/acetone (95/5), then (90/10); GC (80 °C, 6 °C/min) RT =
20.82 min; ATR-FTIR (neat, cm−1) ν 2970, 2930, 1592, 1424, 1282,
1
1
730; H NMR (400 MHz) δ 8.70 (s, 1H), 8.41 (d, J = 7.8 Hz, 1H),
1218, 1181, 1037, 1013, 785, 752; H NMR (400 MHz) δ 7.65 (s,
8.19 (d, J = 7.8 Hz, 1H), 8.03 (d, J = 9.3 Hz, 1H), 7.69−7.65 (m, 3H),
6.62 (d, J = 9.3 Hz, 1H), 6.50−6.47 (m, 2H), 3.99 (s, 3H); 13C NMR
(100 MHz) δ 166.7, 155.9, 152.8, 136.0, 131.0, 130.9, 129.3, 127.6,
126.2, 118.2, 116.5, 112.7, 52.4; MS, m/z (relative intensity) 280 (18),
279 ([M]+, 100), 252 (8), 248 (8), 222 (12), 221 (60), 220 (6), 219
(5), 207 (11), 193 (5), 192 (12), 191 (14), 91 (15); HRMS (ESI+) m/
z calcd for C16H14N3O2 [M + H], 280.108053; found, 280.108245.
3-(1H-Imidazol-1-yl)-6-(3-methylphenyl)pyridazine (2y):
Brown solid. Yield: 130 mg (14%); mp 112−114 °C; FC: elution
with a gradient of pentane/diethyl ether (70/30), then (50/50) and
pentane/acetone (30/70); GC (80 °C, 6 °C/min) RT = 21.40 min;
ATR-FTIR (neat, cm−1) ν 3120, 2960, 1681, 1484, 1435, 1304, 793,
1H), 7.54 (d, J = 9.6 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.27 (t, J = 8.1
Hz, 1H), 6.86 (dd, J = 2.5 and 8.2 Hz, 1H), 6.74 (d, J = 9.6 Hz, 1H),
3.81 (s, 3H), 3.58 (q, J = 7.0 Hz, 4H), 1.18 (t, J = 7.0 Hz, 6H); 13C
NMR (100 MHz) δ 160.1, 156.9, 149.0, 138.3, 129.6, 125.2, 117.8,
115.0, 111.6, 110.2, 55.4, 42.9, 12.9; MS, m/z (relative intensity) 258
(10), 257 ([M]+, 56), 256 (14), 242 (8), 229 (17), 228 (100), 215 (7),
214 (46), 213 (14), 185 (8), 145 (5); HRMS (ESI+) m/z calcd for
C15H20N3O [M + H], 258.160089; found, 258.160453.
3-(2-Methoxyphenyl)-6-(4-methylpiperazin-1-yl)pyridazine
(2t): Yellow solid. Yield: 760 mg (67%); mp 117−118 °C; FC: elution
with a gradient of pentane/acetone (80/20) until 100% acetone, then
actone/methanol (90/10); GC (80 °C, 6 °C/min) RT = 24.10 min;
ATR-FTIR (neat, cm−1) ν 2946, 2804, 1425, 1253, 1240, 1147, 1025,
1
695; H NMR (400 MHz) δ 8.50 (broad s, 1H), 8.02 (d, J = 9.2 Hz,
1H), 7.94 (broad s, 1H), 7.85−7.82 (m, 2H), 7.68 (d, J = 9.2 Hz, 1H),
1
770; H NMR (400 MHz) δ 7.92 (dd, J = 1.5 and 7.5 Hz, 1H), 7.78
I
dx.doi.org/10.1021/jo3022428 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
7.43 (t, J = 7.4 Hz, 1H), 7.34 (broad d, J = 7.6 Hz, 1H), 7.28 (broad s,
1H), 2.46 (s, 3H); 13C NMR (100 MHz) δ 158.7, 150.8, 139.0, 135.0,
131.2, 130.9, 129.1, 127.6, 126.7, 124.0, 119.5, 117.5, 116.1, 21.5;
HRMS (ESI+) m/z calcd for C14H13N4 [M + H], 237.113473; found,
237.113602.
2002, 50, 636−639. (d) Gavande, N.; Johnston, G. A. R.; Hanrahan, J.
R.; Chebib, M. Org. Biomol. Chem. 2010, 8, 4131−4136. (e) Araujo-
Junior, J. X.; Schmitt, M.; Benderittera, P.; Bourguignon, J.-J.
Tetrahedron Lett. 2006, 47, 6125−6128. (f) Maes, B. U. W.;
̀
Lemiere, G. L. F.; Dommisse, R.; Augustyns, K.; Haemers, A.
Tetrahedron 2000, 56, 1777−1781.
(10) Leclerc, J.-P.; Fagnou, K. Angew. Chem., Int. Ed. 2006, 45, 7781−
ASSOCIATED CONTENT
* Supporting Information
■
7786.
S
(11) Composition of the inox grid: iron 72%, chromium 18%, and
nickel 10%.
NMR spectra for aminochloropyridazines 1a−1k and aryl- and
heteroarylpyridazines 2a−2y. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) (a) Gosmini, C.; Ned
2000, 41, 201−203. (b) Gosmini, C.; Ned
Tetrahedron Lett. 2000, 41, 5039−5042.
́
(13) Le Gall, E.; Gosmini, C.; Nedelec, J.-Y.; Perichon, J. Tetrahedron
́
el
́
ec, J.-Y.; Per
́
ichon, J. Tetrahedron Lett.
́
elec, J.-Y.; Perichon, J.
́
́
́
́
AUTHOR INFORMATION
Corresponding Author
*E-mail: leonel@icmpe.cnrs.fr.
■
Lett. 2001, 42, 267−269.
(14) Starting 3-amino-6-chloropyridazines 1a−1k were prepared by
SNAr reactions of amines and 3,6-dichloropyridazine.
Notes
(15) (a) Sengmany, S.; Leo
Pipelier, M.; Thobie-Gautier, C.; Dubreuil, D. J. Org. Chem. 2007, 72,
5631−5636. (b) Sengmany, S.; Le Gall, E.; Leonel, E. Molecules 2011,
16, 5550−5560.
́ ́ ́
nel, E.; Polissaint, F.; Nedelec, J.-Y.;
The authors declare no competing financial interest.
́
ACKNOWLEDGMENTS
■
(16) Predictable issues would be the poisoning of the catalyst by the
starting reagents or reaction products, the possible electrode
passivation, or issues in achieving the extraction of the products, due
to their high polarity. Another sensitive point could concern the
selection of adequate electrode systems to maintain an efficient
catalytic activity all over the electrochemical coupling process.
(17) One can envisage the electrochemical reductive cleavage of the
N−C bonds of the diallylamine moiety.
The authors thank the Agence Nationale de la Recherche
(Programme Blanc “Foldapsules”) for financial support of this
work. The financial support of this project by the CNRS and
the University Paris-Est Cret
́
eil is gratefully acknowledged.
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