Synthesis of substituted 3-amino-6-arylpyridazines via Suzuki reaction

Article abstract of DOI:10.1055/s-1999-3528

Starting from the commercially available 3,6-dichloropyridazine, N₃- substituted 3-amino-6-arylpyridazines were prepared in good yields and under mild conditions by means of two simple steps: a nucleophilic substitution and a palladium-catalyzed Suzuki coupling.

Full text of DOI:10.1055/s-1999-3528

PAPER
1163
Synthesis of Substituted 3-Amino-6-arylpyridazines via Suzuki Reaction
Isabelle Parrot, Yveline Rival,* Camille G. Wermuth
Laboratoire de Pharmacochimie de la Communication Cellulaire ,UMR CNRS ex ERS 655, Université Louis Pasteur, 74 Route du Rhin,
F-67401 Illkirch Cedex, France
Fax+33(388)674794; E-mail: rival@pharma.u-strasbg.fr
Received 18 January 1999; revised 6 March 1999
plication of the Suzuki reaction to 3-chloro-6-methoxy-
Abstract: Starting from the commercially available 3,6-dichloro-
pyridazine and to N3-substituted 3-amino-6-chloropy-
pyridazine, N3-substituted 3-amino-6-arylpyridazines were pre-
ridazines examining the scope and the various conditions
of the reaction.
pared in good yields and under mild conditions by means of two
simple steps: a nucleophilic substitution and a palladium-catalyzed
Suzuki coupling.
In order to study the feasibility of the Suzuki reaction in
the pyridazine series, we examined the coupling reaction
of variously substituted phenylboronic acids with 3-chlo-
ro-6-methoxypyridazine 3 (Scheme 1). One example of
this reaction was described by Quéguiner et al.19 Our re-
sults are summarized in Table 1. Both the palladium com-
plex and a base are essential for the reaction to proceed.
This is in accordance with the observations of Suzuki et
al. who report regularly that the addition of a base greatly
facilitates the cross-coupling of organoboron reagents
with electrophiles by acceleration of the rate of the trans-
metallation step.4
Key words: N3-substituted 3-amino-6-arylpyridazine, dichloropy-
ridazine, 3-chloro-6-methoxypyridazine, 3-amino-6-chloropy-
ridazine, Suzuki cross-coupling, palladium(0) catalysis.
We have recently reported the synthesis of a series of 3-
amino-6-aryl pyridazines derivatives 1 which show acet-
ylcholinesterase inhibiting activities.1,2 The conventional
synthesis of such compounds3 does not allow a rapid ac-
cess to various structural analogs, so we became interest-
ed in developing a new synthetic pathway involving
palladium-catalyzed cross-coupling reactions with orga-
noboranes. The palladium-catalyzed cross-coupling reac-
tion of arylboronic acids with aryl halides is known to
give biaryls.4–7 When using aryl bromides and iodides as
electrophiles, high yields have been achieved with sub-
strates bearing various functional groups on either cou-
pling partner.4,5,7,8 However, much higher energy is
required for the oxidative insertion of palladium catalysts
into the C–Cl bond of aryl chlorides,4–9 and transforma-
tions of these substrates still remain a significant chal-
lenge in synthesis.10 Therefore the use of aryl chlorides in
palladium coupling reactions has been limited to activated
In exploratory experiments we compared the Suzuki cou-
pling using 3-iodo-6-methoxypyridazine to that using 3-
chloro-6-methoxypyridazine. As the yields were found to
be of the same order of magnitude for both halides, we
used subsequently only chloro-substituted pyridazines.
For the phenylboronic acids investigated (Table 1), the
original procedure of Suzuki5 using (Ph3P)4Pd and 2 M
aqueous Na2CO3 in toluene at 110 °C, was found to give
the expected products 4 in 50–90% yields. Sometimes ad-
dition of a small amount of EtOH was effective in facili-
tating the solubility of pyridazine and phenylboronic
acids. Generally some homocoupling occurred, yielding
about 5% of 10, competitive hydrolytic deboronation to
form 11 could also take place if the arylboronic acid bears
electron-attracting substituents (Scheme 1).
chloroarenes
such
as
chloropyridines
and
chlorotriazines11–14 and chloroarenes bearing an electron-
withdrawing group.6,15 Extension of the palladium-cata-
lyzed coupling to pyridazines has mostly been limited to
the coupling of alkynes.16–18 In general, 3-chloro-
pyridazines have been employed as substrates in these re-
actions and the harsh working conditions have often re-
sulted in unacceptably low yields. The only example of a
cross-coupling reaction of arylboronic acid with 3-chloro-
6-methoxypyridazine, using the original conditions de-
scribed by Suzuki et al.5 has been reported by Quéguiner
et al.19 In the present article, we report on the synthetic ap-
Other working conditions, such as the use of aqueous
Ba(OH)2 in DME, which were claimed to accelerate the
coupling rate,20 were less favorable when applied to phen-
ylboronic acid itself, leading only to 50% yield of the de-
sired product, besides the unreacted 3-chloro-6-methoxy-
pyridazine 3 (26%) and the homocoupling product 10
(24%). On the other hand, the coupling of phenylboronic
acid with 3-chloro-6-methoxypyridazine (3) under phase
Scheme 1
Synthesis 1999, No. 7, 1163–1168 ISSN 0039-7881 © Thieme Stuttgart · New York

1164
I. Parrot et al.
PAPER
Table 1 Reaction Conditions for the Pd(0)-Catalyzed Cross-Cou-
pling of 3-Chloro-6-methoxypyridazine (3) with Phenylboronic
Acids
onated acetanilide 11 (R = NHAc). Surprisingly, conduct-
ing the same cross-coupling reaction in the presence of
anhydrous K3PO4 in DMF at 100 °C leads to the py-
ridazinic dimer 10 in 80% yield.
Prod- ArB(OH)2
uct
Reaction Conditionsa
Yieldb
(%)
The transformation of the obtained 6-aryl-3-methoxypy-
ridazines 4 into the corresponding 6-aryl-3-aminated ana-
logues 1 is possible but somewhat lengthy. This involves
the cleavage of the methoxy ether by means of hydroiodic
acid in order to return to the pyridazones 5, the action of
phosphorus oxychloride to yield the iminochlorides 6 and
their nucleophilic substitution with the appropriate amino
side chain, thus furnishing the expected N3-substituted 3-
amino-6-arylpyridazines 1 (Scheme 2).
Base
Solvent
Na2CO3
Na2CO3
toluene/
EtOH
toluene
80
4a
86
50
55
60
Ba(OH)2 DME
c
c
–
–
Na2CO3
Na2CO3
toluene/
EtOH
toluene
4b
4c
4d
4e
4f
60
55
For this reason, in second part of our study, we examined
the applicability of the Suzuki reaction directly to the al-
ready amino-substituted chloropyridazines 8 (Scheme 3).
This alternative approach would allow a faster and simple
two-step access to the unsymmetrical 3,6-disubstituted
pyridazines 1. The synthesis begins with a nucleophilic
monosubstitution of 3,6-dichloropyridazine 2 by an ami-
noalkyl chain affording the 3-amino-6-chloropyridazine 8
in 50–76% yield. Then the palladium-catalyzed cross-
coupling reaction was performed with various phenylbo-
ronic acid using tetrakis(triphenylphosphine)palladium(0)
and an aqueous base such as aqueous 2 M Na2CO3 in tol-
uene at 110 °C for 20h (Method A) as described by Suzu-
ki.5 The expected 3-amino-6-arylpyridazines 1 were
obtained in 35–65% yields (Table 2). The above coupling
conditions were unsuccessful in the case of sterically hin-
dered reactants such as mesitylboronic acid and necessi-
tated the use of aqueous Ba(OH)2 in DME (Method B).
Na2CO3
Na2CO3
Na2CO3
Na2CO3
toluene/
EtOH
toluene/
EtOH
60
81
90
toluene/
EtOH
toluene
a Catalyst: (Ph3P)4Pd.
b Yield of isolated pure product.
c Under phase transfer catalysis conditions (see text).
In conclusion, a variety of 3-amino-6-arylpyridazines 1
have been efficiently prepared by palladium-catalyzed
cross-coupling reactions. The advantages of this method-
ology reside in increased chemical yields, easy operating
conditions, the commercial availability of the arylboronic
acids and 3,6-dichloropyridazine and in shorter synthetic
sequence.
transfer catalysis conditions yielded only 55% of the cor-
responding 3-methoxy-6-phenylpyridazine accompanied
by traces of the pyridazine dimer. The synthesis of the
arylpyridazines 4b, 4c, and 4d implies the use of arylbo-
ronic acids either substituted with electron-withdrawing
groups or bearing sterically hindering substituents in
ortho or ortho’-position, both factors limiting the yields
owing to competitive hydrolytic deboration or to steric
hindrance. Here again the use of a stronger base
[Ba(OH)2] did not improve the yields.
All experiments were carried out under an argon atmosphere. Tolu-
ene, DME, THF were distilled from benzophenone ketyl.
(Ph3P)4Pd, 3,6-dichloropyridazine and arylboronic acids were pur-
chased from Lancaster. Melting points were determined with a Met-
tler FP62 apparatus and are uncorrected. All 1H NMR spectra were
recorded on a Bruker AC 200 (200 MHz) or on a Bruker AC 300
When the reaction was applied to m-N-acetylamidophen-
ylboronic acid (9, R = NHAc) the conventional coupling
conditions produced an appreciable amount of the debor-
Scheme 2
Synthesis 1999, No. 7, 1163–1168 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Scheme 3
Synthesis of Substituted 3-Amino-6-arylpyridazines via Suzuki Reaction
1165
(300MHz) instruments, and chemical shifts are reported in parts per
million (d) relative to TMS for CDCl3 and DMSO-d6 solutions.
Flash chromatography was carried out on silica gel (70–230 mesh
ASTM). Elemental analyses were performed by CNRS (Vernaison)
and are indicated only by the symbols of the elements; analytical re-
sults were within 0.4% of the theoretical values. Organic extracts
were dried over Na2SO4.
The amines 7 were prepared by literature procedures.
3-Benzyl-3-methylaminopropylamine (7a)2,24,25
Yellow oil; yield:75%.
1H NMR (300 MHz, CDCl3): d = 1.63 (quint., 2 H, J = 10.4 Hz),
2.18 (s, 3 H), 2.28 (br s, 2 H), 2.43 (t, 2 H, J = 10.4 Hz), 2.72 (m, 2
H), 3.46 (s, 2 H), 7.29 (m, 5 H).
4-Benzyl-4-methylaminobutylamine (7b)2,26
Yellow oil; yield:75%.
3-Chloro-6-methoxypyridazine (3) was prepared by the literature
procedure;21
mp 92 °C (Lit.22 mp 91–92 °C).
Table 2 Pd(0)-Catalyzed Cross-Coupling of 3-Alkyl-6-chloroaminopyridazines 8 with Phenylboronic Acids
Yieldc (%)
Mpd (°C)
a
Product
ArB(OH)2
R
Reaction
Conditionsb
1a
1b
A
A
66
45
159
45
1c
A
A
40
35
195
95
1d
1e
1f
A
45
128
dec.
205
A
B
0
65
1g
A
A
60
50
1h
220
a Catalyst: (Ph3P)4Pd.
b A: (Ph3P)4Pd, Na2CO3 2M, ArB(OH)2, toluene, 20h, 110°C; B:(Ph3P)4Pd, Ba(OH)2, 8H2O, ArB(OH)2, DME, 20h, 110°C.
c Yield of isolated pure product.
d All melting points refer to hydrochlorides.
Synthesis 1999, No. 7, 1163–1168 ISSN 0039-7881 © Thieme Stuttgart · New York

1166
I. Parrot et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 1.63 (quint, 2 H, J = 10.4 Hz),
2.18 (s, 3 H), 2.28 (br s, 2 H), 2.43 (t, 2 H, J = 10.4 Hz), 2.72 (m, 2
H), 3.46 (s, 2 H), 7.29 (m, 5 H).
3-Methoxy-6-(3-N-acetylphenyl)pyridazine (4g)
1H NMR (DMSO-d6, 200 MHz): d = 2.06 (s, 3 H), 4.07 (s, 3 H),
7.31 (d, 1 H, J = 9.5 Hz), 7.60 (m, 4 H), 8.06 (d, 1 H, J = 9 Hz).
3-(1,2,3,4-Tetrahydroisoquinolin-2-yl)propylamine (7c)2,27
Colourless oil; yield:85%.
1H NMR (300 MHz, CDCl3): d = 1.60–1.79 (m, 4 H), 2.57 (m, 2 H),
2.70–2.82 (m, 4 H), 2.90 (t, 2 H, J = 5.3 Hz), 3.63 (s, 2 H), 6.98–
7.10 (m, 4 H).
3,6-di-(4-methoxyphenyl)pyridazine (10)
1H NMR (300 MHz, CDCl3): d = 4.19 (s, 6 H), 7.11 (d, 2 H, J = 9.42
Hz), 8.60 (d, 2 H, J = 9.42 Hz).
13C NMR (300 MHz, CDCl3): d = 55.17, 118.28, 127.48, 152.65,
165.59.
2-(1-Benzylpiperidin-4-yl)ethylamine (7d)2,28–32
Yield: 53%; mp (dihydrochloride) 137 °C (Lit.2,28–32 mp 175–
178 °C).
Anal. calc. for C10H10N2O4: C, 55.03; H, 4.62; N, 25.67. Found: C,
54.98; H, 4.78; N, 25.46.
1H NMR (200 MHz, CDCl3) : d = 1.18–1.45 (m, 5 H), 1.59-1.64 (m,
2 H), 1.85–1.96 (m, 2 H), 2.18 (br s, 2 H), 2.63–2.71 (m, 2 H), 2.80–
2.86 (m, 2 H), 3.44 (s, 2 H), 7.18–7.29 (m, 5 H).
3-Alkylamino-6-chloropyridazines 8; General Procedure
To 3,6-dichloropyridazine (2; 500 mg, 3.36 mmol, 1 equiv) in a 50
mL two-necked flask equipped with a magnetic stirrer were added
amine 7 (3 equiv), H2O (1.7 mL) and then 37% HCl (0.07 mL)
through the neck of the flask. The mixture was stirred between 80
and 100 °C for 24 to 48 h. The reaction was allowed to cool to r.t.
and the solvent was removed in vacuo. The residue was diluted with
H2O, brought to pH 11 with alkali and extracted with EtOAc
(3x15 mL). The organic phase was concentrated and the crude prod-
uct was purified by chromatography on silica gel eluting with a
9:1:2 (v/v) mixture of EtOAc/MeOH/Et3N.
3-Methoxy-6-phenylpyridazines 4; General Procedure
Argon was passed for 30 mn through a suspension of 3 (500 mg,
3.46 mmol, 1 equiv), arylboronic acid (1.15 equiv), aq 2 M Na2CO3
solution (3.7mL, 7.33mmol, 2.12 equiv), toluene (20mL) and a
small amount of EtOH in order to ensure an homogenous reaction
medium. (Ph3P)4Pd (123 mg, 0.11 mmol, 0.031 equiv) was added
and the mixture was heated at 110 °C for at least 16 h. The toluene
was removed in vacuo and the residue was diluted with H2O and ex-
tracted with EtOAc (3x5 mL). The organic layer was washed with
H2O (3x5 mL) and concentrated in vacuo to give a residue which
was purified by column chromatography (silica gel, CH2Cl2 /
EtOAc, 95:5).
3-[(3-Benzyl-3-methylamino)propylamino]-6-chloropyridazine
(8a)
Reaction conditions:95–100 °C, 24 h; yield:50%.
1H NMR (CDCl3, 200 MHz): d = 1.82 (m, 2 H), 2.25 (s, 3 H), 2.54
(t, 2 H, J = 6.2 Hz), 3.50 (m, 4 H), 6.07 (s, 1 H), 6.47 (d, 1 H, J = 9.5
Hz), 7.09 (d, 1 H, J = 9 Hz), 7.29 (m, 5 H).
3-Methoxy-6-(4-chlorophenyl)pyridazine (4b)
Mp 151 °C.
3-[(4-Bbenzyl-4-methylamino)butylamino]-6-chloropyridazine
(8b)
Reaction conditions:95–100 °C, 72 h; yield:76%.
1H NMR (DMSO-d6, 200 MHz): d = 4.07 (s, 3 H), 7.33 (d, 1 H,
J = 9.5 Hz), 7.59 (m, 2 H), 8.09 (m, 2 H), 8.19 (d, 1 H, J = 9 Hz).
Anal. calc. for C11H9ClN2O: C, 59.87; H, 4.11; N, 12.69. Found: C,
59.76; H, 4.28; N, 12.43.
1H NMR (CDCl3, 300 MHz): d = 1.67 (m, 4 H), 2.21 (s, 3 H), 2.45
(t, 2 H, J = 36 Hz), 3.45 (m, 4 H), 6.08 (s, 1 H), 6.48 (d, 1 H, J = 14
Hz), 7.10 (d, 1 H, J = 14 Hz), 7.31 (m, 5 H).
3-Methoxy-6-(3,5-ditrifluoromethylphenyl)pyridazine (4c)
Mp 97 °C.
6-Chloro-3-[3-(1,2,3,4-tetrahydroisoquinolin-2-yl)propylami-
no]pyridazine (8c)
Reaction conditions:95–100 °C, 48 h; yield:50%.
1H NMR (CDCl3, 300 MHz): d = 1.93 (m, 2 H), 2.72 (t, 2 H,
J = 6.99 Hz), 2.80 (t, 2 H, J = 6.33 Hz), 2.95 (t, 2 H, J = 7.26 Hz),
3.57 (m, 2 H), 3.67 (s, 2 H), 6.28 (s, 1 H), 6.44 (d, 1 H, J = 9.4 Hz),
7.04 (m, 2 H), 7.15 (m, 3 H).
1H NMR (DMSO-d6, 200 MHz): d = 4.10 (s, 3 H), 7.43 (d, 1 H,
J = 9.5 Hz), 8.24 (s, 1 H), 8.50 (d, 1 H, J = 9.5 Hz), 8.74 (s, 2 H).
Anal. calc. for C13H8F6N2O: C, 48.46; H, 2.50; N, 8.69. Found: C,
48.69; H, 2.72; N, 8.50.
3-Methoxy-6-(2,4,6-trimethylphenyl)pyridazine (4d)
Mp 201 °C.
1H NMR (DMSO-d6, 200 MHz): d = 1.93 (s, 6 H), 2.28 (s, 3 H),
4.06 (s, 3 H), 6.96 (s, 2 H), 7.28 (d, 1 H, J = 9 Hz), 7.54 (d, 1 H, J = 9
Hz).
3-[(2-Benzylpiperidin-4-yl)ethylamino]-6-chloropyridazine
(8d)
Reaction conditions:95–100 °C, 24 h; yield:72%.
1H NMR (CDCl3, 200 MHz): d 1.32 (m, 3 H), 1.65 (m, 4 H), 1.96
(t, 2 H, J = 7.5 Hz), 2.89 (d, 2 H, J = 12 Hz), 3.42 (m, 4 H), 4.73 (s,
1 H), 6.61 (d, 1 H, J = 9.5 Hz), 7.16 (d, 1 H, J = 9.5 Hz), 7.29 (m, 5
H).
Anal. calc. for C14H16N2O•HCl•0.25H2O: C, 62.45; H, 6.55; N,
10.40. Found: C, 62.28; H, 6.59; N, 10.13.
3-Methoxy-6-(4-methoxyphenyl)pyridazine (4e)
Mp 134 °C.
3-Alkylamino-6-phenylpyridazines 1a–e,g,h; General Proce-
dure
1H NMR (DMSO-d6, 200 MHz): d = 3.81 (s, 3 H), 4.04 (s, 3 H),
7.06 (m, 2 H), 7.25 (d, 1 H, J = 9.5 Hz), 8.01 (m, 2 H), 8.09 (d, 1 H,
J = 9.5 Hz).
Method A: Argon was passed through a suspension of 8 (3.46
mmol, 1 equiv), arylboronic acid (3.98 mmol, 1.15 equiv), aq 2 M
Na2CO3 solution (3.7 mL, 7.34 mmol, 2.12 equiv), toluene (20 mL)
and if necessary EtOH (to facilitate the solubility of pyridazine and
the phenylboronic acid used) for 30 min. (Ph3P)4Pd (0.10 mmol,
0.031 equiv) was added and the mixture was heated at 110 °C for 24
h. The toluene was removed in vacuo, the residue diluted with H2O
and extracted with EtOAc (3x5 mL). The organic layer was washed
with H2O (3x5 mL) and concentrated in vacuo. The crude product
was purified by chromatography on silica gel using a 9:1:2 (v/v)
mixture of EtOAc/MeOH/Et3N. The corresponding hydrochlorides
were prepared by treating the free base dissolved in Et2O and/or
Anal. calc. for C12H12N2O2: C, 66.65; H, 5.59; N, 12.96. Found: C,
66.59; H, 5.64; N, 12.90.
3-Methoxy-6-(4-methylphenyl)pyridazine (4f)
Mp 109.5 °C.
1H NMR (DMSO-d6, 200 MHz): d = 2.36 (s, 3 H), 4.06 (s, 3 H),
7.30 (m, 3 H), 7.95 (m, 2 H), 8.12 (d, 1 H, J = 6 Hz).
Anal. calc. for C12H12N2O: C, 71.98; H, 6.04; N, 13.99. Found: C,
72.07; H, 6.17; N, 13.64.
Synthesis 1999, No. 7, 1163–1168 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Substituted 3-Amino-6-arylpyridazines via Suzuki Reaction
1167
EtOAc with gaseous HCl or with 2.1 equiv of 37% HCl. The col-
1 H), 6.77 (d, 1 H, J = 9.5 Hz), 7.30 (m, 5 H), 7.62 (d, 1 H, J = 9.5
lected solids were recrystallized from i-PrOH/Et2O.
Hz), 7.88 (s, 1 H), 8.46 (s, 2 H).
3-[(3-Benzyl-3-methylamino)propylamino]-6-phenylpy-
ridazine (1a)
1h•2 HCl; mp 220 °C (i-PrOH).
Anal. calc. for C26H26N4F6•2 HCl: C, 53.71; H, 4.85; N, 9.64.
Found: C, 53.83; H, 5.04; N, 9.43.
1H NMR (CDCl3, 300 MHz): d = 1.87 (m, 2 H), 2.26 (s, 3 H), 2.55
(t, 2 H, J = 15.8 Hz), 3.53 (m, 4 H), 5.89 (s, 1 H), 6.59 (d, 1 H, J = 14
Hz), 7.42 (m, 9 H), 7.99 (d, 2 H, J = 13.5 Hz).
3-[2-(1-Benzylpiperidin-4-yl)ethylamino]-6-(2,4,6-trimeth-
ylphenyl)pyridazine (1f)
1a•2HCl; mp 159 °C (i-PrOH).
Method B: The procedure is almost same as Method A except for
the solvent and base used. To a degassed and repeatedly flushed
with Ar mixture of 8 (3.46 mmol, 1 equiv), arylboronic acid (3.98
mmol, 1.15 equiv) in DME (20 mL), was added Ba(OH)2•8
H2O(1.15 equiv) and the system was degassed again. Then
(Ph3P)4Pd (0.10 mmol, 0.031 equiv) was added and after heating at
110 °C for 24 h, the resulting mixture and the corresponding hydro-
chloride were worked up as described in Method A.
Anal. calc. for C21H24N4•2 HCl•0.5 H2O: C, 60.87; H, 6.57; N,
13.52. Found: C, 60.96; H, 6.61; N, 13.46.
3-[(4-Benzyl-4-methylamino)butylamino]-6-phenylpyridazine
(1b)
1H NMR (CDCl3, 300 MHz): d = 1.70 (m, 4 H), 2.21 (s, 3 H), 2.44
(t, 2 H, J = 10.5 Hz), 3.47 (m, 4 H), 5.40 (s, 1 H), 6.60 (d, 1 H, J = 14
Hz), 7.47 (m, 9 H), 7.98 (d, 2 H, J = 9.8 Hz).
1b•2 HCl; mp 45 °C (i-PrOH).
1H NMR (CDCl3, 300 MHz): d = 1.40 (m, 3 H), 1.70 (m, 4 H), 2.01
(m, 8 H), 2.34 (s, 3 H), 2.92 (d, 2 H, J = 11 Hz), 3.47 (m, 4 H), 4.75
(s, 1 H), 6.69 (d, 1 H, J = 9 Hz), 6.95 (s, 2 H), 7.09 (d, 1 H, J = 9
Hz), 7.33 (m, 7 H).
Anal. calc. for C22H26N4•2 HCl•H2O): C, 60.41; H, 6.91; N, 12.81.
Found: C, 60.10; H, 6.63; N, 12.54.
3-[3-(1,2,3,4-tetrahydroisoquinolin-2-yl)propylamino]-6-phe-
nylpyridazine (1c)
1f•2 HCl (i-PrOH); mp could not be determined due to decomposi-
tion.
1H NMR (CDCl3, 300 MHz): d = 1.95 (m, 2 H), 2.75 (m, 4 H), 2.93
(m, 2 H), 3.54 (m, 1 H), 3.65 (m, 3 H), 6.22 (s, 1 H), 6.51 (m, 1 H),
6.61 (d, 1 H, J = 9 Hz), 7.09 (m, 4 H), 7.46 (m, 3 H), 7.97 (d, 2 H,
J = 12 Hz).
Anal. calc. for C27H34N4•2 HCl•1.5 H2O: C, 63.02; H, 7.64; N,
10.89. Found: C, 62.77; H, 7.59; N, 10.71.
1c•2 HCl; mp 195 °C (i-PrOH).
References
Anal. calc. for C22H24N4•2 HCl•2 H2O: C, 58.27; H, 6.27; N, 12.36.
Found: C, 58.12; H, 6.27; N, 13.23.
(1) Wermuth, C. G.; Contreras, J. M.; Pinto, J.; Guilbaud, P.;
Rival, Y.; Bourguignon, J. J. Acta Pharmaceutica
Hungarica. 1996, S3-S8.
(2) Contreras, J. M.; Rival, Y.; Chayer, S.; Wermuth, C. G. J.
Med. Chem.1999; 42, 730.
(3) Wermuth, C. G.; Schlewer, G.; Bourguignon, J. J.; Maghioros,
G.; Bouchet, M. J.; Moire, C.; Kan, J. P.; Worms, P.; Biziere,
K. J. Med. Chem. 1989, 32, 528.
3-[2-(1-Benzylpiperidin-4-yl)ethylamino]-6-(2-methylphe-
nyl)pyridazine (1d)
1H NMR (CDCl3, 300 MHz): d = 1.30 (m, 3 H), 1.69 (m, 4 H), 1.98
(t, 2 H, J = 9 Hz), 2.41 (s, 3 H), 2.91 (d, 2 H, J = 11 Hz), 3.50 (m, 4
H), 4.73 (s, 1 H), 6.69 (d, 1 H, J = 9 Hz), 7.40 (m, 9 H).
1d•2 HCl; mp 95 °C (i-PrOH).
(4) Martin, A. R.; Yang, Y. Acta. Chem. Scand. 1993, 47, 221.
(5) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth.Commun. 1981, 11,
513.
(6) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(7) Miyaura, N. Fine Chemical. 1997, 26, 5.
(8) Stanforth, S. P. Tetrahedron 1998, 54, 263.
(9) Fitton, P.; Rick, E. A. J. Organometal. Chem. 1971, 28, 287.
(10) Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047.
(11) Mitchell, M. B.; Wallbank, P. J. Tetrahedron Lett. 1991, 32,
2273.
Anal. calc for C25H30N4•2 HCl•H2O: C, 62.88; H, 7.18; N, 11.74.
Found: C, 62.44; H, 7.58; N, 11.18.
3-[2-(1-Benzylpiperidin-4-yl)ethylamino]-6-(2-methoxyphe-
nyl)pyridazine (1e)
1H NMR (CDCl3, 300 MHz): d = 1.30 (m, 3 H), 1.67 (m, 4 H), 1.97
(t, 2 H, J = 8 Hz), 2.91 (d, 2 H, J = 12 Hz), 3.45 (m, 4 H), 3.86 (s, 3
H), 4.72 (s, 1 H), 6.64 (d, 1 H, J = 9 Hz), 7.00 (d, 1 H, J = 6 Hz),
7.09 (t, 1 H, J = 10 Hz), 7.31 (m, 6 H), 7.8 (d, 1 H, J = 9 Hz), 7.89
(d, 1 H, J = 6 Hz).
1e•2 HCl; mp 128 °C (i-PrOH).
(12) Ali, N. M.; Mckillop, A.; Mitchell, M. B.; Rebelo, R. A.;
Wallbank, P. J. Tetrahedron 1992, 48, 8117.
(13) Janietz, D.; Bauer, M. Synthesis 1993, 33.
(14) Achab, S.; Guyot, M.; Potier, P. Tetrahedron Lett. 1993, 34,
2127.
(15) Shen, W. Tetrahedron Lett. 1997, 38, 5575.
(16) Toussaint, D.; Suffert, J.; Wermuth, C. G. Heterocycles 1994,
38, 1273.
(17) Ohsawa, A.; Abe, Y.; Igeta, H. Chem. Pharm. Bull. 1980, 28,
3488.
(18) Konno, S.; Sagi, M.; Siga, F.; Yamanaka, H. Heterocycles
1992, 34, 225.
Anal. calc. for C25H30N4O•2 HCl•3 H2O: C, 56.70; H, 7.23; N,
10.58. Found: C, 57.36; H, 7.04; N, 10.59.
3-[2-(1-Benzylpiperidin-4-yl)ethylamino]-6-(2-naphthyl)py-
ridazine (1g)
1H NMR (CDCl3, 300 MHz): d = 1.27 (m, 3 H), 1.67 (m, 4 H), 2.01
(t, 2 H, J = 11.3 Hz), 2.92 (d, 2 H, J = 11.3 Hz), 3.53 (m, 4 H), 4.72
(s, 1 H), 6.74 (d, 1 H, J = 9.5 Hz), 7.31 (m, 5 H), 7.51 (m, 2 H), 7.77
(d, 1 H, J = 9.5 Hz), 7.92 (m, 3 H), 8.23 (d, 1 H, J = 8.6 Hz), 8.39
(s,1 H).
1g•2 HCl; mp 205 °C (i-PrOH).
(19) Turck, A., Plé, N., Mojovic, L., Quéguiner, G. Bull. Soc.
Chim. Fr. 1993, 130, 488.
Anal. calc. for C25H26N4•2 HCl•1.25 H2O: C, 62.24; H, 6.48; N,
11.60. Found: C, 62.43; H, 6.51; N, 11.15.
(20) Watanabe, T., Miyaura, N., Suzuki, A. Synlett 1992, 207.
(21) Salisbury J. Heterocycl. Chem. 1967, 4, 431.
(22) Steck; Brundage J. Am. Chem. Soc. 1959, 81, 6511.
(23) Ohsawa, A. Chem. Pharm. Bull. 1978, 26, 2550.
(24) Shapiro, S. L.; Rose, I. M.; Freedman, L. J. Am. Chem. Soc.
1959, 81, 3083.
3-[2-(1-Benzylpiperidin-4-yl)ethylamino]-6-(3,5-ditrifluorome-
thylphenyl)pyridazine (1h)
1H NMR (CDCl3, 300 MHz): d = 1.30 (m, 3 H), 1.67 (m, 4 H), 1.70
(t, 2 H, J = 7.9 Hz), 2.89 (d, 2 H, J = 11 Hz), 3.48 (m, 4 H), 5.45 (s,
Synthesis 1999, No. 7, 1163–1168 ISSN 0039-7881 © Thieme Stuttgart · New York

1168
I. Parrot et al.
PAPER
(31) Sugimoto, H.; Tsuchiya, Y.; Sugumi, H.; Higurashi, K.;
(25) Ueda, T.; Ishizaki, K. Chem. Pharm. Bull. 1967, 15, 228.
(26) Secor, H. V.; Izac, R. R.; Hassam, S. B.; Frisch, A. F. J.
Labelled Compd. Radiopharm. 1994, 34, 421.
(27) Finch, N.; Gemenden, C. W. J. Org. Chem. 1973, 38, 437.
(28) Profitt, J. A.; Watt, D. S. J. Org. Chem. 1975, 40, 127.
(29) Eckhardt, W.; Grob, C. A. Helv. Chim. Acta. 1974, 57, 2339.
(30) Garratt, P. J.; Doecke, C. W.; Weber, J. C.; Paquette, L. A.
J. Org. Chem. 1986, 51, 449.
Karibe, N.; Limura, Y.; Sasaki, A.; Kawakami, Y.; Nakumura,
T.; Araki, S.; Yamanishi, Y.; Yamatsu, K. J. Med. Chem.
1990, 33, 1880.
(32) New, J. S.; Yevich, J. P. Synthesis 1983, 388.
Article Identifier:
1437-210X,E;1999,0,07,1163,1168,ftx,en;Z00499SS.pdf
Synthesis 1999, No. 7, 1163–1168 ISSN 0039-7881 © Thieme Stuttgart · New York