Synthesis of original trifluoromethylated 6-aryl-pyridazines fused with thiazolidine or 1,2,4-triazole

Article abstract of DOI:10.1055/s-2005-918433

An efficient synthesis of original 8-trifluoromethyl-7H-thiazolo[3,2-b]-and 1,2,4-triazolo[4,3-b]pyridazines is described. Starting from the 4-trifluoromethyl-4,5-dihydropyridazin-3-one, the methodology involves a five-membered ring closure, based on the

Full text of DOI:10.1055/s-2005-918433

PAPER
103
Synthesis of Original Trifluoromethylated 6-Aryl-pyridazines Fused with
Thiazolidine or 1,2,4-Triazole
Synthesis of
O
rig
é
inal 8-Trif
l
d
uoromethyla
r
ted7
H
-t
i
hiazolo
c
[
3,2-
b
]
-
or 1,2,4-t
B
riazolo[4,3-
b
]pyr
r
idazines
u
.
lé,a Jean-Philippe Bouillon,1 Eric Nicolaï,b Charles Portella*a
a
Laboratoire ‘Réactions Sélectives et Applications’ associé au CNRS (UMR 6519), Université de Reims Champagne-Ardenne,
Faculté des Sciences, B.P. 1039, 51687 Reims Cedex 2, France
b
CEREP S.A., 128 rue Danton, B.P. 50601, 92506 Rueil-Malmaison Cedex, France
Fax +33(3)26913166; E-mail: charles.portella@univ-reims.fr
Received 15 June 2005
moiety due to our easy and efficient synthesis of 4,5-dihy-
dropyridazin-3-ones.7
Abstract: An efficient synthesis of original 8-trifluoromethyl-7H-
thiazolo[3,2-b]- and 1,2,4-triazolo[4,3-b]pyridazines is described.
Starting from the 4-trifluoromethyl-4,5-dihydropyridazin-3-one,
the methodology involves a five-membered ring closure, based on
the reaction of a bis(electrophilic) reagent with an exocyclic het-
eroatom linked to position 3 and the endocyclic nitrogen at position
2 of the pyridazine nucleus.
Thus compound 2 was the common starting material for
the syntheses of both 7H-thiazolo[3,2-b]pyridazines and
1,2,4-triazolo[4,3-b]pyridazines. The presence of two nu-
cleophilic centers, one exocyclic heteroatom linked to po-
sition 3 and the endocyclic nitrogen at position 2, would
allow double nucleophilic substitution with a bis(electro-
phile).
Key words: fluorine, nitrogen heterocycles, pyridazine derivatives,
thiazolo[3,2-b]pyridazine, 1,2,4-triazolo[4,3-b]pyridazine
CF3
CF3
The 6-aryl-1,2,4-triazolo[4,3-b]pyridazine moiety is an
interesting pharmacophore, well-known for its anxiolytic
and antihypertensive properties.2 Some of its derivatives
are also useful agents for the treatment of asthma.3 More-
over, because fluorine incorporation on a molecule could
considerably modify its physico-chemical and biological
properties, the use of fluorine in potential drugs is increas-
ing.4 For instance, CL 218,872 represents such a trifluo-
romethylated pharmacophore possessing the ability to
bind the benzodiazepine receptors in rat brain (Figure 1),
which appears to be useful against anxiety.5
O
F3C
F
SEt
SEt
X
Z
ref. 7a
Ar
Y
NH
N
N
Ar
N
1
2
4, 8–10
Ar = p–BrC6H4
Scheme 1
A thionation reaction with Lawesson’s reagent9 was ap-
plied to compound 2 to give the corresponding 4,5-dihy-
dropyridazin-3-thione 3 (Scheme 2). Then, 3 was reacted
with methyl a-bromoacetate giving the 7H-thiazolo[3,2-
b]pyridazine 4 in a totally regioselective reaction. The
ring closure was then performed by an in situ amidifica-
tion reaction. The presence of an acidic hydrogen at posi-
tion 4 of 3 (a to the trifluoromethyl group), avoids the
formation of a quaternary ammonium salt in the final
product.10
N
N
F3C
N
CL 218,872
N
Me
Figure 1
Several trifluoromethylated 1,2,4-triazolo[4,3-b]pyrid-
azines have already been synthesized2b,6 but never at the
position proposed here. Our previous report dealt with the
synthesis of 4-trifluoromethylated pyridazines from per-
fluoroketene dithioacetal 1 in an original and efficient
three-step pathway.7 The current paper addresses the syn-
thesis of more sophisticated bis(heterocycles) 4 and 8–10
(Scheme 1). Two general methodologies can be consid-
ered to prepare these targets based on the priority order of
ring construction. Rather than a five- then six-membered
ring construction,8 we chose to first build the pyridazine
CF3
CF3
S
S
a
b
2
NH
N
Ar
N
Ar
N
O
3 (84%)
4 (57%)
Ar = p–BrC6H4
Scheme 2 Reagents and conditions: (a) Lawesson’s reagent, tolu-
ene, reflux, 2 h; (b) BrCH2CO2Me, DMF, 100 °C, 5 h
The 1,2,4-triazolo[4,3-b]pyridazines synthesis is depicted
in Scheme 3. First, the pyridazin-3-one 5, obtained by ox-
idation of 2 with copper(II) chloride, was reacted with
phosphorous oxy chloride to yield the 3-chloropyridazine
6.7 Then nucleophilic addition of hydrazine to 6 followed
by chloride elimination, led to 3-hydrazinopyridazine 7 in
SYNTHESIS 2006, No. 1, pp 0103–0106
x
x
.
x
x
.2
0
0
5
Advanced online publication: 27.10.2005
DOI: 10.1055/s-2005-918433; Art ID: Z11705SS
© Georg Thieme Verlag Stuttgart · New York

104
C. Brulé et al.
PAPER
CF3
N
N
N
8 (80%)
Ar
N
Me
d
CF3
CF3
CF3
CF3
H
O
Cl
N
N
a
b
c
e
NH2
2
NH
NH
N
N
N
N
Ar
N
Ar
N
Ar
N
Ar
N
O
5 (87%)
6 (91%)
7 (85%)
f
9 (84%)
CF3
Ar = p–BrC6H4
N
N
Ar
g
N
X
10a: X = NH2 (82%)
10b: X = NH2⋅2HCl (100%)
Scheme 3 Reagents and conditions: (a) CuCl2, CH3CN, reflux, 7 h; (b) POCl3, 70–80 °C, 4 h; (c) NH2NH2·H2O, CH3CN, 80 °C, 3 h; (d)
AcOH, 100 °C, 6 h; (e) 1,1¢-carbonyldiimidazole, CH3CN, reflux, 4 h; (f) BrCN, EtOH, r.t., 5 h; (g) HCl (6 N), i-PrOH, r.t., 20 min
ppm relative to an internal standard: TMS (0.00 ppm) or CHCl3
(7.27 ppm) for 1H and 13C NMR and fluorotrichloromethane (0.00
ppm) for 19F NMR spectra. Coupling constants are reported in Hz.
All reactions were monitored by TLC with Merck silica gel 60 F254
0.25 mm plates. IR spectra were recorded with a Avatar 320 Fourier
transform spectrometer. LRMS were obtained with either a mass
spectrometer coupled with gas chromatography (GC-MS) Thermo-
quest Trace GC 2000 series, in EI mode, or a mass spectrometer
quadripole Micromass 2MD (ESI+) coupled with liquid chromatog-
raphy Waters (LC-MS). HRMS were recorded on a Q-TOF Micro-
mass spectrometer in positive electrospray mode (ES+, EC 30 V).
Elemental analyses were performed with a Perkin-Elmer CHN 2400
apparatus. Petroleum ether used had a bp range 40–60 °C.
good yield. To obtain 1,2,4-triazolo[4,3-b]pyridazines,
the triazolo ring must be formed from the reaction of a
1,1-bis(electrophile) reagent with the 1,4-bis(nucleophile)
7. In this way, the 3-methyl-1,2,4-triazolo[4,3-b]py-
ridazine 8 was prepared by heating 7 in an acetic acid me-
dium. The reaction of 7 with 1,1¢-carbonyldiimidazole
yielded the heterocycle 9 which exists in two tautomeric
forms. Analytical data highlight the predominance of the
keto form. The IR spectrum shows the carbonyl vibration
at 1724 cm–1 and the NH at 3135 cm–1. Moreover, the 1H
NMR spectrum in DMSO-d6 shows a broad singlet at 13.1
ppm corresponding to the amide proton; such observa-
tions were consistent with what had been reported previ-
ously.11 The reaction of 7 with cyanogen bromide gave the
1,2,4-triazolo[4,3-b]pyridazine 10a with a free primary
amine function.12 Then, simple treatment with an acidic
solution of isopropanol, quantitatively yielded its dihy-
drochloride form 10b.
For analytical data of compounds 5 and 6 see reference 7.
6-(4¢-Bromophenyl)-4-trifluoromethyl-4,5-dihydro-2H-py-
ridazin-3-thione (3)
To a solution of 4,5-dihydropyridazin-3-one 2 (300 mg, 0.9 mmol)
in toluene (5 mL), was added Lawesson’s reagent (416 mg, 1.0
mmol). The mixture was stirred at 110 °C for 2 h. After cooling, the
residue was washed with brine (4 mL). The organic layer was ex-
tracted with Et2O (2 × 5 mL), dried over MgSO4, filtered, and evap-
orated in vacuo. The product was purified by silica gel
chromatography to give a yellow solid.
The presence of an aryl bromide on these compounds both
allows further chemical transformations like palladium-
catalyzed reactions and could have biological relevance.
Indeed Albright and co-workers reported antihypertensive
effects related to the presence of an electron-withdrawing
group on the phenyl ring of such compounds.2a
Yield: 255 mg (84%); mp 220–222 °C; Rf 0.6 (petroleum ether–
EtOAc, 80:20).
IR (KBr): 3253 (NH), 2942, 1584, 1476, 1342 cm–1.
1H NMR (acetone-d6): d = 3.00 (br s, 1 H, NH), 3.28 (dd, J = 7.7,
18.3 Hz, 1 H, 5-H), 3.42 (dd, J = 3.3, 18.3 Hz, 1 H, 5-H), 4.1 (m, 1
H, 4-H), 7.67 (d, J = 8.5 Hz, 2 H, Ar-H), 7.85 (d, J = 8.5 Hz, 2 H,
Ar-H).
13C NMR (acetone-d6): d = 21.7 (q, J = 2.7 Hz, 5-C), 47.8 (q,
J = 26.7 Hz, 4-C), 125.3 (CBr), 125.6 (q, J = 281.2 Hz, CF3), 128.8,
132.7 (Ar-C), 135.0 (1¢-C), 152.7 (6-C), 185.3 (3-C).
The procedures depicted allow an efficient access, under
mild conditions, to new biologically interesting com-
pounds such as 4 and 8–10. The presence of a trifluoro-
methyl group, in such an original position on 6-aryl-
pyridazines fused with thiazolidine and 1,2,4-triazole
make them good candidates for further biological evalua-
tion.
19F NMR (acetone-d6): d = –67.9 (d, J = 9.5 Hz).
MPs were determined on a Büchi apparatus and are uncorrected. 1H,
13C, and 19F nuclear NMR spectra were recorded with either a Bruk-
er AC-250 or AC-400 spectrometer. Chemical shifts are reported in
Anal. Calcd for C11H8BrF3N2S: C, 39.19; H, 2.39; N, 8.31. Found:
C, 39.14; H, 2.26; N, 8.33.
Synthesis 2006, No. 1, 103–106 © Thieme Stuttgart · New York

PAPER
Synthesis of Original 8-Trifluoromethylated 7H-thiazolo[3,2-b]- or 1,2,4-triazolo[4,3-b]pyridazines
105
6-(4¢-Bromophenyl)-8-trifluoromethyl-7H-thiazolo[3,2-b]py-
ridazin-3-one (4)
19F NMR (CDCl3): d = –65.3 (s).
To a solution of 4,5-dihydropyridazin-3-thione 3 (200 mg, 0.6
mmol) in DMF (5 mL) was added methyl a-bromoacetate (68 mL,
0.7 mmol). The mixture was stirred at 100 °C for 5 h. After cooling,
DMF was evaporated. The mixture was diluted in Et2O (10 mL) and
neutralized, at 0 °C, with a sat. soln of NaHCO3. After decantation
and separation, the aqueous layer was washed with Et2O (3 × 10
mL). The combined organic layers were dried over Na2SO4, filtered,
and evaporated in vacuo. The product was purified by silica gel
chromatography to give a solid.
6-(4¢-Bromophenyl)-8-trifluoromethyl-1,2,4-triazolo[4,3-b]py-
ridazin-3-one (9)
To a solution of 3-hydrazinopyridazine 7 (85 mg, 0.25 mmol) in
MeCN (1.5 mL), was added 1,1¢-carbonyldiimidazole (83 mg, 0.50
mmol). The mixture was refluxed for 4 h. After cooling to r.t., the
residue was washed with brine (2 mL). The organic layer was then
extracted with EtOAc (3 × 3 mL), dried over Na2SO4, filtered, con-
centrated in vacuo, and recrystallized from MeCN.
Yield: 75 mg (84%); Rf 0.3 (cyclohexane–EtOAc, 60:40).
Yield: 129 mg (57%); mp 190–192 °C; Rf 0.4 (petroleum ether–
EtOAc, 80:20).
IR (KBr): 1720, 1668, 1612, 1381 cm–1.
1H NMR (DMSO-d6): d = 3.62 (s, 2 H, 7-H), 4.07 (s, 2 H, 2-H), 7.71
(d, J = 8.5 Hz, 2 H, Ar-H), 7.85 (d, J = 8.5 Hz, 2 H, Ar-H).
13C NMR (DMSO-d6): d = 23.1 (7-C), 30.0 (2-C), 91.9 (q, J = 33.8
Hz, 8-C), 124.7 (q, J = 269.7 Hz, CF3), 124.9 (CBr), 128.5, 131.6
(Ar-C), 133.4 (1¢-C), 135.9 (NCS), 150.7 (6-C), 165.9 (3-C).
19F NMR (DMSO-d6): d = –61.8 (s).
IR (KBr): 3135 (NH), 1724 (CO) cm–1.
1H NMR (DMSO-d6): d = 7.77 (d, J = 8.4 Hz, 2 H, Ar-H), 8.05 (d,
J = 8.4 Hz, 2 H, Ar-H), 8.16 (s, 1 H, 7-H), 13.1 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 120.9 (q, J = 273.5 Hz, CF3), 121.1 (q,
J = 4.8 Hz, 7-C), 124.8 (CBr), 125.2 (q, J = 35.8 Hz, 8-C), 129.1,
132.1 (Ar-C), 132.5 (1¢-C), 133.0 (NCN), 149.2, 149.3 (3-C, 6-C).
19F NMR (DMSO-d6): d = –64.1 (s).
LC-MS (ES+): m/z (%) = 361 [M + 1 + H+], 359 [M – 1 + H+].
HRMS: m/z calcd for C12H6BrF3N4O [M + H]+: 358.9755; found:
GC-MS (EI): m/z (%) = 378 [M+ + 1], 376 (100) [M+ – 1], 349, 309
358.9770.
[M+ + 1 – CF3], 221 [M+ – PhBr], 183.
Anal. Calcd for C13H8BrF3N2OS: C, 41.40; H, 2.14; N, 7.43. Found:
C, 41.37; H, 1.95; N, 7.27.
3-Amino-6-(4¢-bromophenyl)-8-trifluoromethyl-1,2,4-triazo-
lo[4,3-b]pyridazine (10a)
A solution of 3-hydrazinopyridazine 7 (2.85 g, 8.6 mmol) and BrCN
(1.09 g, 10.3 mmol) in EtOH (80 mL) was stirred at r.t. for 5 h. The
mixture was then cooled with an ice bath and the pH adjusted to 10
by the addition of a soln of KOH (2 M). The precipitate formed was
removed by filtration, washed with cold Et2O, and recrystallized
from MeCN to yield a yellow crystalline powder.
6-(4¢-Bromophenyl)-3-hydrazino-4-trifluoromethylpyridazine
(7)
To a solution of 3-chloropyridazine 6 (500 mg, 1.5 mmol) in MeCN
(10 mL), was added NH2NH2·H2O (360 mL, 7.5 mmol). The mixture
was heated at 80 °C for 3 h. The solvent was removed in vacuo. The
resulting residue was diluted in CH2Cl2 (10 mL) and washed with a
sat. soln of NaHCO3 (8 mL). After decantation and separation, the
aqueous layer was washed with CH2Cl2 (2 × 10 mL). The combined
organic layers were dried over Na2SO4, filtered, and concentrated in
vacuo. The residue can be chromatographed on silica gel or used di-
rectly for the next step. Purification yielded a white solid.
Yield: 2.52 g (82%); mp >220 °C.
IR (KBr): 3425 (NH2), 3098, 1653, 1138 cm–1.
1H NMR (DMSO-d6): d = 6.97 (br s, 2 H, NH2), 7.80 (d, J = 8.4 Hz,
2 H, Ar-H), 8.05 (s, 1 H, 7-H), 8.24 (d, J = 8.4 Hz, 2 H, Ar-H).
13C NMR (DMSO-d6): d = 115.1 (q, J = 4.9 Hz, 7-C), 121.4 (q,
J = 273.6 Hz, CF3), 124.7 (q, J = 35.6 Hz, 8-C), 125.0 (CBr), 129.4,
132.0 (Ar-C), 132.6 (1¢-C), 134.6 (NCN), 149.9, 151.3 (3-C, 6-C).
19F NMR (DMSO-d6): d = –63.3 (s).
LC-MS (ES+): m/z (%) = 360 [M + 1 + H+], 358 [M – 1 + H+].
HRMS: m/z calcd for C12H7BrF3N5 [M + H]+: 357.9915; found:
357.9906.
Yield: 425 mg (85%); mp 91 °C.
1H NMR (DMSO-d6): d = 4.7 (br s, 2 H, NH2), 7.66 (d, J = 8.0 Hz,
2 H, Ar-H), 8.02 (d, J = 8.0 Hz, 2 H, Ar-H), 8.08 (s, 1 H, 5-H), 8.4
(br s, 1 H, NH).
13C NMR (DMSO-d6): d = 112.3 (m, 4-C), 121.6 (m, 5-C), 122.5
(CBr), 122.6 (q, J = 273.3 Hz, CF3), 127.7, 131.8 (Ar-C), 134.8 (1¢-
C), 149.0 (6-C), 153.6 (3-C).
19F NMR (DMSO-d6): d = –66.4 (s).
3-Amino-6-(4¢-bromophenyl)-8-trifluoromethyl-1,2,4-triazo-
lo[4,3-b]pyridazine Dihydrochloride (10b)
Compound 10a (2.52 g, 7.0 mmol) was stirred in HCl–i-PrOH (6 N;
10 mL) at r.t. for 20 min. Alcohol was then removed and the result-
ing crystals were washed with cold Et2O (10 mL), filtered, and dried
in vacuo.
6-(4¢-Bromophenyl)-3-methyl-8-trifluoromethyl-1,2,4-triazo-
lo[4,3-b]pyridazine (8)
3-Hydrazinopyridazine 7 (100 mg, 0.3 mmol) was heated at 100 °C
in an excess of AcOH (0.5 mL) for 6 h. The mixture was cooled to
0 °C, diluted with EtOAc (5 mL), and neutralized with a sat. soln of
Na2CO3 (3 mL). After separation, the aqueous layer was washed
with EtOAc (3 × 10 mL). The combined organic layers were dried
over MgSO4, filtered, concentrated in vacuo, and recrystallized
from MeCN to give a white solid.
Yield: 3.03 g (100%).
IR (KBr): 3420 (NH), 3039, 2655, 1694, 1349, 1146 cm–1.
1H NMR (DMSO-d6): d = 7.5 (m, 2 H, NH2), 7.80 (d, J = 8.4 Hz, 2
H, Ar-H), 8.18 (s, 1 H, 7-H), 8.24 (d, J = 8.4 Hz, 2 H, Ar-H).
Yield: 86 mg (80%); mp >220 °C; Rf 0.4 (cyclohexane–EtOAc,
50:50).
Anal. Calcd for C12H9BrCl2F3N5: Cl, 16.4. Found: Cl, 16.2.
1H NMR (CDCl3): d = 2.93 (s, 3 H, CH3), 7.74 (d, J = 8.4 Hz, 2 H,
Ar-H), 7.77 (s, 1 H, 7-H), 7.91 (d, J = 8.4 Hz, 2 H, Ar-H).
Acknowledgment
13C NMR (CDCl3): d = 10.0 (CH3), 115.7 (q, J = 4.8 Hz, 7-C),
120.9 (q, J = 274.0 Hz, CF3), 126.6 (CBr), 127.3 (q, J = 36.9 Hz, 8-
C), 128.7 (Ar-C), 132.2 (1¢-C), 132.8 (Ar-C), 138.6 (NCN), 148.4,
152.0 (3-C, 6-C).
We are grateful to ANRT and CEREP Company for financial sup-
port of this work.
Synthesis 2006, No. 1, 103–106 © Thieme Stuttgart · New York

106
C. Brulé et al.
PAPER
(7) (a) Our method: Brulé, C.; Bouillon, J.-P.; Nicolaï, E.;
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Synthesis 2006, No. 1, 103–106 © Thieme Stuttgart · New York