Synthesis of aryltrifluoromethylpyridazines application to the synthesis of rod-like molecules as liquid crystals diazines part 46

Article abstract of DOI:10.1002/jhet.5570430516

Conjugated oligomers with a trifluoromethylpyridazine unit have been synthesized by Suzuki cross-coupling reaction. These oligomers could be used as building block for construction of supramolecules or as liquid crystals when they are substituted by long

Full text of DOI:10.1002/jhet.5570430516

Sep-Oct 2006
1243
Synthesis of Aryltrifluoromethylpyridazines
Application to the Synthesis of Rod-like Molecules as Liquid Crystals
Diazines Part 46
Sylvain Achelle,a Nelly Plé,*a Alain Turck,a Jean-Philippe Bouillon,a Charles Portellab
a) Université de Rouen, Institut de Recherche en Chimie Organique Fine
(I.R.C.O.F.), BP 08, F-76131 Mont Saint-Aignan, France.
b) Laboratoire Réactions Sélectives et Applications, UMR CNRS 6519,
Université de Reims, Faculté des Sciences B.P. 1039, F-51687 Reims Cedex 2, France.
nelly.ple@insa-rouen.fr.; Tel +33-2-35-52-29-02; Fax +33-2-35-52-29-62
Received November 30, 2005
CF3
CF3
Cl
CF3
Suzuki
cross-coupling
Suzuki
cross-coupling
R'
R''
X
R'
R'
N
N
N N
N
N
X = H, Br, OR
Conjugated oligomers with a trifluoromethylpyridazine unit have been synthesized by Suzuki cross-
coupling reaction. These oligomers could be used as building block for construction of supramolecules or
as liquid crystals when they are substituted by long chain alkoxy groups.
J. Heterocyclic Chem., 43, 1243 (2006).
Introduction.
Several applications could be envisaged according to
the nature of the para-substituents. Long chain alkoxy
groups would bring liquid crystal properties to these rod-
like core compounds, whereas hydroxyl groups would
allow further functionalization and their incorporation
into supramolecules.
There is a widespread interest in the synthesis of new
conjugated oligoarenes containing electron-deficient
heterocycles in their backbone. Oligomers incorporating
pyridine, bipyridine, quinoline, triazine and more recently
pyrazine moieties have been previously described mainly
for the elaboration of electronic devices [1-5].
Results and Discussion.
Since the last two decades such structures have received
considerable attention due to their role in the design and
generation of new materials which are used in various
fields such as electroluminescent materials [6], organic
conductors [7], optoelectronic devices [8], nonlinear optic
(NLO) materials [9], liquid crystals [10]. They are also
used as building blocks for supramolecules [11]. In such
molecules, azaheterocycles can be used as the electron-
deficient units and fluorine atoms to increase the electron
deficiency of these ꢀ-conjugated moieties.
For the synthesis of such oligomers, 6-aryl-3-chloro-4-
trifluoromethylpyridazines were chosen as central unit.
Substituted phenyl moieties with long terminal alkyl- or
alkoxy chains were introduced by cross-coupling
reactions and should induce liquid crystallinity.
The synthetic methods to access to 6-aryl-3-chloro-4-
trifluoromethylpyridazines, include either forming the
heterocycle moiety by using fluorinated precursors or
introducing the trifluoromethyl group into the preformed
pyridazine.
Incorporation of a heteroaryl moiety such as pyridine,
pyrimidine or pyrazine into the ꢀ-conjugated system have
been investigated to synthesize liquid crystals [10f,12].
With the aim to synthesize new conjugated structures
containing a ꢀ-deficient aromatic, we report here the
synthesis of a new family of rod-like oligomers including
a trifluoromethyl-pyridazine as central unit and substi–
tuted by benzene rings with various electron-donor groups
at the para position (Scheme 1).
Using the first strategy, the synthesis of 6-(p-bromo-
phenyl)-3-chloro-4-trifluoromethylpyridazine 1 has been
previously described from perfluoroketene dithioacetal as
Scheme 2
Cl
CF3
Ar
O
CF3
(v)
(iii) (iv)
(ii)
(i)
CF3 SEt
SEt
N
N
SEt
O
F
Scheme 1
Ar
(i) ArCOMe, KH, THF, 0-25°, 10h
(ii)TFA, H2O, reflux, 10h
(iii) NH2NH2, PTSA, PhMe, reflux
(iV) CuCl2, MeCN, reflux, 7h
(V) POCl3, 70-80°, 4h
CF3
1 Ar = p-Br-C6H4
2 Ar = Ph
52%
28%
3 Ar = p-C7H15O-C6H4 29%
R
R'
N
N

1244
S. Achelle, N. Plé, A. Turck, J-P. Bouillon, C. Portella
Vol 43
starting material [13a,b]. According to this methodology,
two 6-aryl-3-chloro-4-trifluoromethylpyrid-azines 2, 3
were obtained in five steps with 28-52% overall yields
(Scheme 2). A recent paper reports a new procedure to
prepare 4-trifluoromethyl-4,5-dihydro-pyridazin-3-ones,
which can be an interesting alternative to the first three
steps depicted in Scheme 2 [13c].
would induce a difference in reactivity. In the Suzuki
cross-coupling reaction, the bromine atom is known to be
more reactive than the chlorine, however in this case, the
chlorine atom is attached to the ꢀ-deficient pyridazine,
substituted by a very strong electron-withdrawing group
such as the trifluoromethyl group. Thus the reactivity
could be reversed between the chlorine and the bromine
atom. To test this reactivity we have investigated the
coupling reaction of 1 with p-methoxyphenyl boronic
acid.
Using the second strategy, compound 2 has been
obtained by reaction of 3-chloro-4-iodo-6-phenyl-
pyridazine
4 with methyl chlorodifluoroacetate as
trifluoromethylating agent [14]. This methodology has
been previously used to access to trifluoromethyl
pyrazines and pyrimidines [15]. The metallation of
commercial 3-chloro-6-phenylpyridazine was carried out
with 1.2 equivalent of lithium 2,2,6,6-tetramethyl-
piperidide (LTMP) at -70° for 1.5 hour, followed by
reaction with iodine (1.1 eq.) as the electrophile and gave
regioselectively the 4-iodo derivative 4 in 56% yield.
Heating methyl chlorodifluoroacetate with 4 in the
presence of anhydrous potassium fluoride and copper (I)
iodide in dimethylformamide led to the corresponding
trifluoromethyl compound 2 in moderate yield with
simultaneous elimination of carbone dioxide and methyl
iodide (Scheme 3).
When 1 equivalent of p-methoxyphenyl boronic acid
was used, we obtained a mixture of compounds resulting
from bicoupling and monocoupling either with the
bromine or the chlorine atom. All attempts to control the
selectivity of this reaction using various experimental
conditions were unsuccessful.
In order to improve the reactivity, we have attempted
the replacement of the chlorine atom by an iodine
atom. Treatment of 1 with acetic acid, sulphuric acid
and sodium iodide under reflux of acetonitrile did not
lead to the expected iodo derivative but gave the
reduction of the carbon chlorine bond, affording 8 in
good yield (Scheme 5).
Scheme 3
Cl
Cl
Cl
I
CF3
1) 1.2 eq. LTMP/THF/-70°C/1.5h
2) 1.1 eq. I2/ -70°/1.5h
56%
N
N
N
N
ClCF2COOMe/KF/CuI
N
N
115°/3h/DMF
65%
Ph
Ph
Ph
2
4
Scheme 4
B(HO)2
R'
N
N
N
N
R'
R
Cl
CF3
R
Pd(Ph3)4/CsCO3/Na2CO3/Toluene/reflux
CF3
5
6
7
R = H
R = H
R' = H
R' = OMe 95%
65%
2 R = H
3 R = OC7H15
R = OC7H15 R' = OMe 75%
The coupling reaction of 2 and 3 with aryl boronic
acids was carried out under standard aqueous Suzuki
cross coupling conditions to afford 5-7 in good yields
(Scheme 4).
For the synthesis of longer oligomers problems would
arise from use of compound 1 as a building block. This
compound bears two different halogen atoms which
Scheme 5
CF3
H
CF3
CH3COOH/H2SO4/NaI
Br
Cl
Br
CH3CN/reflux/5h
N
N
N
N
78%
8
1

Sep-Oct 2006
Synthesis of Aryltrifluoromethylpyridazines
1245
When a four-fold excess of boronic acid was used, the
compound 9 was obtained in good yield (86%). A further
cleavage of the methoxy group using pyridinium chloride
at 210° for 1 hour led to the dihydroxy compound 10 in
87% yield (Scheme 6).
crystalline to isotropic transition. During the cooling
run, the smallest oligomer 14 exhibited a nematic
mesophase, indicated by the typical Schlieren texture
from 86.9° (ꢀH = 17.70 kJ mol-1) to the clearing
temperature determined for 117.3° (ꢀH = 0.53 kJ
Scheme 6
4 eq.
(OH)2B
OMe
N
N
N
N
MeO
OMe
Br
Cl
Pd(PPh3)4/Na2CO3/Toluene/reflux/30h
86%
CF3
CF3
1
9
Pyridinium chloride
210°C / 1h.
87%
N
N
HO
OH
CF3
10
In order to synthesize rod-like molecules, which could
have liquid crystalline properties and to evaluate the
influence of various terminal chains, we have investigated
the coupling reaction of 1 with alkyl- or alkoxyphenyl-
boronic acids leading to compounds 11-15 with good
yields (Scheme 7).
mol-1). Oligomer 15
showed also a crystalline
nematic mesophase; the melting peak was observed
at 99.46° (ꢀH = 11.73 kJ mol-1) and clearing
temperature at 117.9° (ꢀH = 0.10 kJ mol-1) during
the heating run, while the cooling run revealed the
crystallization peak at 86.64° (ꢀH = 7.40 kJ mol-1).
Scheme 7
4 eq.
(OH)2B
R
N
N
N
N
R
R
Br
Cl
CF3
Pd(PPh3)4/Na2CO3/Toluene/reflux/30h
CF3
74%
1
11 R = C4H9
12 R = C12H25
13 R = C8H13
14 R = OC8H17
83%
71%
78%
83%
15 R = OC12H25
Conclusion.
The synthesis of compound 13 has been achieved
by coupling reaction of 1 with the 4-(oct-1-ynyl)-
phenylboronic acid 16 obtained from the corres-
ponding bromo derivative in 71% yield. Compounds
14 and 15 were synthesized either by coupling
reaction of the corresponding alkoxyboronic acid or
Starting from 6-aryl-3-chloro-4-trifluoromethylpyri-
dazines as building blocks, we have described, using
palladium-catalyzed cross-coupling reactions, a general
synthetic route to access to various trifluoromethylated
polyarylpyridazines. These oligomers could find
applications in the construction of supramolecules, or as
crystal liquids when they are substituted in terminal
position by long chain alkoxy groups.
by
a Williamson reaction from the dihydroxy
derivative 10 (yield: 91%).
Then the liquid crystalline property of these oligomers
was investigated, their melting behaviour was examined
by differential scanning calorimetry (DSC) and polar-
ization microscopy [16].
EXPERIMENTAL
Despite the nature and the lengh of the terminal
alkyl group, compounds 11-13 revealed no liquid
Melting points were determined on a Electrothermal 1100
1
instrument. The H, 13C and 19F nmr spectra were recorded on a
1
Bruker AC 300 (300 MHz H, 75 MHz 13C, 282.5 MHz 19F)
crystalline behaviour; they featured only
a

1246
S. Achelle, N. Plé, A. Turck, J-P. Bouillon, C. Portella
Vol 43
instrument. Microanalyses were performed on a Carlo Erba
CHNOS 1160 apparatus. The IR spectra were obtained as
potassium bromide pellets with a Perkin-Elmer 16 PC FT-IR
spectrometer. Mass spectra were recorded on an ATI-Unicam
Automass® apparatus.
We thank Pr. André-Jean Attias and Dr. David Kreher (UMR
7610-CNRS, Pierre et Marie Curie University) for their
collaboration and the determination of the transition
temperatures measured with the polarising microscope and using
DSC.
122.5, 127.2, 129.3, 129.3, 131.3, 133.7, 151.0, 159.3; 19F nmr
(deuteriochloroform): ꢀ -66.1; ir (potassium bromide) 1151,
1396, 1449, 1520, 3054, 3074 cm-1; HRMS (ESI) calcd for
C11H7ClF3N2 m/e = 259.0250; found 259.0244.
3-Chloro-6-(4-heptyloxyphenyl)-4-trifluoromethylpyridazine
(3).
Preparation of 3 according to the general procedure A gave
after purification 3.47 g of 3 (93%) as a colorless solid, mp 84-
1
85°; H nmr (deuteriochloroform): ꢀ 0.91 (t, J = 6.6 Hz, 3H,
CH3), 1.3-1.6 (m, 8H, 4 x CH2), 1.84 (m, 2H, OCH2CH2), 4.05
(t, J = 6.6 Hz, 2H, OCH2), 7.06 (d, J = 9.0 Hz, 2H, 2 x CH),
8.02 (q, JH,F = 0.7 Hz, 1H, H5), 8.06 (d, J = 9.0 Hz, 2H, 2 x
General Procedure A for Synthesis of 3-Chloro-4-trifluoro-
methylpyrazines.
4
CH); 13C nmr (deuteriochloroform): ꢀ 14.0, 22.6, 25.9, 29.0,
29.1, 31.7, 68.2, 115.2, 121.1, 121.6, 125.8, 128.6, 128.7,
149.9, 158.7, 161.9; 19F nmr (deuteriochloroform): ꢀ -66.1;
GC-MS: m/e (%) = 374 [M++1], 372, 276, 274 (100), 246,
118, 57.
A mixture of (2H)-pyridazin-3-one prepared according to
procedures reported in the literature [13a], (4 mmoles, 1 equiv.)
and phosphorus oxychloride (40 mmoles, 10 equiv.) was heated
at 70-80° for 4 hours, under argon atmosphere. After cooling,
the excess of phosphorus oxychloride was evaporated in vacuo.
The residue was purified by silica gel column chromatography
(eluent petroleum ether:ethyl acetate (95:5)) to give the 3-
chloro-4-trifluoromethylpyridazines 1-3.
Anal. Calcd. for C18H20ClF3N2O: C, 57.99; H, 5.41; N, 7.51.
Found: C, 58.30; H, 5.52; N, 7.34.
3-Chloro-4-iodo-6-phenylpyridazine (4).
General Procedure
trifluoromethyl-pyrazines with Arylboronic Acids Under Suzuki
Conditions.
B for Cross-coupling of 3-Chloro-4-
A solution of 3.93 mL of n-butyllithium (1.6 M in hexane,
6.29 mmoles, 1.2 equiv.) was added to a cold (ꢁ30°), stirred
and anhydrous mixture of THF (40 mL) and 1.19 mL of
2,2,6,6-tetramethylpiperidine (TMPH) (7.1 mmoles, 1.3
equiv.) under an atmosphere of dry nitrogen. The mixture was
warmed to 0°. After 30 minutes, the mixture was cooled to
-78° and added to a cold (-78°) solution of 3-chloro-6-
phenylpyridazine (1 g, 5.24 mmoles) dissolved in THF (5 mL).
Then, the mixture was stirred for 90 minutes. At -70°, iodine
(1.50 g, 5.91 mmoles, 1.1 equiv.) was introduced and stirring
was continued for 90 minutes at this temperature. Hydrolysis
A mixture of 3-chloro-4-trifluoromethylpyrazine, arylboronic
acid (n equiv.), tetrakis(triphenylphosphine)palladium(0) (0.1
equiv.), Cesium carbonate (1 equiv.), aqueous 2 M potassium
carbonate (1 equiv.) and ethanol (1 mL) in degassed toluene (15
mL) was heated to reflux under nitrogen for 30 hours. The
reaction mixture was cooled, diluted with 20 mL of a mixture of
water and ethyl acetate (1:1) and the organic layer separated.
The aqueous layer was extracted with ethyl acetate (3x20 mL).
The combined organic extracts were dried over magnesium
sulfate and evaporated.
was then carried out at -70° using
a solution of
THF:EtOH:HCl (4:1:1). Temperature was raised to room
temperature, the mixture was made slightly basic with
saturated sodium hydrogen carbonate solution. The solution
was decolorized with sodium thiosulfate and evaporated nearly
to dryness. The residue was extracted with dichloromethane
(3x20 mL), the combined organic extracts were then dried over
magnesium sulfate and evaporated. The product was purified
by column chromatography (silica gel, eluent: cyclohexane:
ethylacetate (1:1)) to give 0.93 g of 4 (56%) as a colorless
6-(p-Bromophenyl)-3-chloro-4-trifluoromethylpyridazine (1).
[13a]
Preparation of 1 according to the general procedure A was
described in the literature.
3-Chloro-6-phenyl-4-trifluoromethylpyridazine (2) [13b].
Method 1.
1
solid, mp 138-139°. H nmr (deuteriochloroform): ꢀ 7.54 (m,
3H, HPh), 8.02 (m, 2H, HPh), 8.36 (s, 1H, H5); 13C nmr
(deuteriochloroform): ꢀ 104.9, 127.6, 129.6, 131.2, 134.1,
136.9, 158.2, 159.2; ir (potassium bromide) 603, 696, 771,
808, 1039, 1156, 1362, 1440, 1541 cm-1.
Anal. Calcd. for C10H6ClIN2 (316.4) C, 37.95 H, 1.91 N,
8.85. Found C, 38.05 H, 1.97 N, 8.92.
Preparation of 2 according to the general procedure A gave
after purification 2.20 g of 2 (85%) as a colorless solid, mp 159-
160° (litt. 152°). [13b]
Method 2.
A mixture of 4 (0.50 g, 1.58 mmoles), methyl chloro-
difluoroacetate (0.46 g, 3.16 mmoles), potassium fluoride (0.18
g, 3.16 mmoles), and copper(I) iodide (0.45 g, 2.37 mmoles) in
DMF (4 mL) under nitrogen atmosphere was heated at 115° for
3 hours. After cooling to room temperature, the solvent was
removed under reduced pressure. The organic extract was
washed with water, dried over magnesium sulfate and
evaporated. The crude product was purified by column
chromatography (silica gel, eluent cyclohexane:ethyl acetate
(7:3)) to give 224 mg (65%) of 2 as a colorless solid, mp 159-
3,6-Diphenyl-4-trifluoromethylpyridazine (5).
Cross-coupling reaction of 2 (50 mg, 0.2 mmole) with
phenylboronic acid (100 mg, 0.52 mmole) according to general
procedure B (t = 30 hours) gave after purification by column
chromatography (silica gel, eluent dichloromethane:ethyl
acetate (1:1)) 101 mg (65%) of 5 as a colorless solid, mp 108-
1
109°. H nmr (deuteriochloroform): ꢀ 7.55 (m, 6H, HPh), 7.65
(m, 2H, HPh), 8.15 (s, 1H, H5), 8.19 (m, 2H, HPh); 13C nmr
(deuteriochloroform): ꢀ 115.9, 121.0, 121.2, 124.8, 127.6,
128.5, 128.7, 130.1, 131.3, 135.2, 136.0, 157.4, 158.7; 19F nmr
1
160°. H nmr (deuteriochloroform): ꢀ 7.59 (m, 3H, HPh), 8.10
(m, 3H, HPh + H5); 13C nmr (deuteriochloroform): ꢀ 121.1,

Sep-Oct 2006
Synthesis of Aryltrifluoromethylpyridazines
1247
(deuteriochloroform): ꢀ -60.3; ir (potassium bromide) 1452,
1403, 1377, 1263, 1136, 1092, 1047, 910, 763, 695, 674 cm-1.
Anal. Calcd. for C17H11F3N2 (300.09) C, 68.00 H, 3.69 N,
9.33. Found: C, 67.79 H, 3.61 N, 9.21.
6-(4'-Methoxybiphenyl-4-yl)-3-(4-methoxyphenyl)-4-trifluoro-
methylpyridazine (9).
Cross-coupling reaction of 1 (100 mg, 0.13 mmole) with 4-
methoxyphenylboronic acid (200 mg, 1.32 mmoles) according
to the general procedure B (t = 30 hours) gave after
purification by column chromatography (silica gel, eluent
dichloromethane:ethyl acetate (4:1)) 114 mg (86%) of 9 as a
yellow solid, mp 106-107°. 1H nmr (deuteriochloroform): ꢀ
8.18 (d, J = 7.9 Hz, 2H, HPh), 8.08 (s, 1H, H5), 7.70 (d, J = 7.9
Hz, 2H, HPh), 7.56 (m, 4H, HPh), 6.97 (m, 4H, HPh), 3.81 (s,
3H, OCH3), 3.79 (s, 3H, OCH3); 13C nmr (deuteriochloroform):
ꢀ 55.7, 55.8, 114.2, 114.8, 116.5, 120.8, 121.3, 125.0, 127.8,
128.1, 128.6, 131.2, 132.8, 133.4, 143.5, 156.8, 157.9, 160.1,
161.2; ir (potassium bromide) 714, 822, 918, 1010, 1031,
1133, 1178, 1256, 1394, 1496, 1602 cm-1.
3-(4-Methoxyphenyl)-6-phenyl-4-trifluoromethylpyridazine (6).
Cross-coupling reaction of 2 (78 mg, 0.3 mmole) with 4-
methoxyphenylboronic acid (100 mg, 0.66 mmole) according
to the general procedure B (t = 30 hours) gave after
purification by column chromatography (silica gel, eluent
dichloromethane) 95 mg (95%) of 6 as a pale yellow solid, mp
1
112-113°. H nmr (deuteriochloroform): ꢀ 3.81 (s, 3H, OCH3),
7.07 (d, J = 8.7 Hz, 2H, HPh), 7.60 (m, 3H, HPh), 7.66 (d, J =
8.7 Hz, 2H, HPh), 8.14 (s, 1H, H5), 8.20 (m, 2H, HPh); 13C nmr
(deuteriochloroform): ꢀ 55.8, 114.2, 116.5, 121.1, 121.3,
124.9, 127.5, 128.3, 129.7, 131.2, 135.3, 157.0, 158.3, 161.3;
ir (potassium bromide) 696, 771, 833, 1024, 1151, 1242, 1378,
1404, 1510, 1609 cm-1.
Anal. Calcd for C25H19F3N2O2 (436.14) C, 78.51 H, 5.80 N,
7.32. Found C, 78.30 H, 5.81 N, 7.25.
3-(4-Hydroxyphenyl)-6-(4'-hydroxybiphenyl-4-yl)-4-trifluoro-
methylpyridazine (10).
Anal. Calcd. for C18H13F3N2O (330.10) C, 65.45 H, 3.97 N,
8.48. Found: C, 65.31 H, 3.82 N, 8.40.
Pyridine hydrochloride (10 g) heated at 220° for 15 minutes
was added to 9 (80 mg, 0.18 mmol). The mixture was
maintained at this temperature for 1 hour then poured on to ice.
The solution was extracted with ether (3x20 mL), the
combined organic extracts were then dried over magnesium
sulfate and evaporated. After purification by column
chromatography (silica gel, eluent dichloromethane) 67 mg
(87%) of 10 was obtained as a pale yellow solid, mp > 250°.
1H nmr (acetone-d6): ꢀ 6.85 (d, J = 8.7 Hz, 2H, HPh), 6.90 (d, J
= 8.7 Hz, 2H, HPh), 7.42 (d, J = 8.7 Hz, 2H, HPh), 7.51 (d, J =
8.7 Hz, 2H, HPh), 7.70 (d, J = 8.7 Hz, 2H, HPh), 8.26 (d, J = 8.7
Hz, 2H, HPh), 8.37 (s, 1H, H5), 8.55 (s, 1H, OH), 8.80 (s, 1H,
OH); 13C nmr (acetone-d6): ꢀ 116.4, 117.2, 121.9 (2C), 122.7,
128.1, 128.3, 128.8, 128.9, 129.4, 132.1, 134.4, 144.3, 157.8,
158.7, 159.1, 160.1.
6-(4-Heptyloxyphenyl)-3-(4-methoxyphenyl)-4-trifluoromethyl-
pyridazine (7).
Cross-coupling reaction of 3 (50 mg, 0.13 mmole) with 4-
methoxyphenylboronic acid (50 mg, 0.33 mmole) according
to the general procedure B (t = 30 hours) gave after
purification by column chromatography (silica gel, eluent
dichloromethane:ethyl acetate (4:1)) 89 mg (75%) of 7 as a
1
yellow solid, mp 88-89°. H nmr (deuteriochloroform): ꢀ 0.84
(t, J = 7.5 Hz, 3H, CH3), 1.30 (m, 8H, 4xCH2), 1.74 (m, 2H,
CH2), 3.82 (s, 3H, OCH3), 3.97 (t, J = 6.4 Hz, 2H, OCH2), 6.98
(m, 4H, HPh), 7.54 (d, J = 8.3 Hz, 2H, HPh), 7.98 (s, 1H, H5),
8.06 (d, J = 8.3 Hz, 2H, HPh); 13C nmr (deuteriochloroform): ꢀ
14.5, 23.0, 26.4, 29.5, 29.6, 32.2, 55.7, 68.6, 114.2, 115.6,
120.2, 121.3, 127.4, 128.5, 128.9, 131.1, 143.7, 156.2, 157.9,
162.2, 161.9; ir (potassium bromide) 828, 1077, 1135, 1179,
1247, 1267, 1392, 1418, 1506, 1608, 2856, 2931 cm-1.
Anal. Calcd. for C25H27F3N2O2 (442.22) C, 67.55 H, 6.12 N,
6.30. Found C, 67.75 H, 6.21 N, 6.42.
This compound was used without further purification for the
synthesis of 14.
6-(4'-Butylbiphenyl-4-yl)-3-(4-butylphenyl)-4-trifluoromethyl-
pyridazine (11).
3-(4-Bromophenyl)-5-trifluoromethylpyridazine (8).
Cross-coupling reaction of 1 (150 mg, 0.47 mmole) with 4-
butylphenylboronic acid (356 mg, 0.80 mmole) according to
the general procedure B (t = 30 hours) gave after purification
by column chromatography (silica, eluent dichloromethane)
169 mg (74%) of 11 as a colorless solid, mp 118-119°. 1H nmr
(deuteriochloroform): ꢀ 0.87 (m, 6H, 2 x CH3), 1.32 (m, 4H, 2
x CH2), 1.58 (m, 4H, 2 x CH2), 2.61 (m, 4H, 2 x CH2), 7.23
(m, 4H, HPh), 7.51 (m, 4H, HPh), 7.71 (d, J = 7.1 Hz, 2H, HPh),
8.07 (s, 1H, H5), 8.17 (d, J = 7.1 Hz, 2H, HPh); 13C nmr
(deuteriochloroform): ꢀ 14.4 (2C), 22.8, 33.8, 34.0, 35.7, 35.9,
120.7, 120.8, 127.4, 127.9, 128.1, 128.8, 129.5, 129.6, 133.4,
133.7, 137.6, 143.4, 144.0, 145.2, 157.3, 158.1; 19F nmr
(deuteriochloroform): ꢀ -60.3; ir (potassium bromide) 807,
1048, 1139, 1172, 1260, 1396, 1605, 2855, 2928, 2958 cm-1.
Anal. Calcd for C31H31F3N2 (488.24) C, 76.21 H, 6.40 N,
5.73 Found C, 75.88 H, 6.06 N, 5.23.
A stirred solution of 1 (100 mg, 0.3 mmole), Sodium iodide
(150 mg, 1.0 mmole), acetic acid (0.5 mL), concentrated
sulphuric acid (2 μL) in acetonitrile (5 mL) was refluxed for 5
hours. After cooling, acetonitrile was evaporated under
reduced pressure and the residue partitioned between
dichloromethane (20 mL) and water (20 mL). The mixture was
made slightly basic with saturated sodium hydrogen carbonate
solution. The aqueous solution was extracted with
dichloromethane (3 x 20 mL). The extracts were dried over
magnesium sulfate, filtered and the solvent was evaporated.
The residue was purified by column chromatography (silica
gel, eluent dichloromethane) to give 69 mg (78%) of 8 as a
1
colorless solid, mp 174-175°. H nmr (deuteriochloroform): ꢀ
7.73 (d, J = 8.8 Hz, 2H, HPh), 8.03 (s, 1H, H4), 8.05 (d, J = 8.8
Hz, 2H, HPh), 9.42 (s, 1H, H6); 13C nmr (deuteriochloroform): ꢀ
118.1 (2C), 123.0, 125.0, 127.8, 129.0, 131.6, 144.1, 157.9; ir
(potassium bromide) 829, 1041, 1072, 1101, 1113, 1138, 1180,
1272, 1342, 1400, 1591 cm-1.
6-(4'-Dodecylbiphenyl-4-yl)-3-(4-dodecylphenyl)-4-trifluoro-
methylpyridazine (12).
Anal. Calcd. for C11H6BrF3N2 (303.08) C, 43.59 H, 2.00 N,
9.24. Found C, 43.68 H, 2.15 N, 8.89.
Cross-coupling reaction of 1 (130 mg, 0.38 mmole) with 4-
dodecylphenylboronic acid (440 mg, 1.52 mmoles) according to

1248
S. Achelle, N. Plé, A. Turck, J-P. Bouillon, C. Portella
Vol 43
the general procedure B (t = 30 hours) gave after purification by
column chromatography (silica, eluent petrolueum ether:ethyl
acetate (95:5)) 224 mg (83 %) of 12 as a pale yellow solid, mp
82-83°. 1H nmr (deuteriochloroform): ꢀ 0.87 (m, 6H, 2 x CH3),
1.26 (m, 36H, 18 x CH2), 1.64 (m, 4H, 2 x CH2), 2.64 (m, 4H, 2
x CH2), 7.23 (m, 4H, HPh), 7.51 (m, 4H, HPh), 7.71 (d, J = 7.1
chloroform): ꢀ 14.5, 23.1, 26.5, 29.7, 29.8, 32.2, 68.5, 95.7,
114.7, 115.3, 118.8, 122.7, 127.7, 127.9, 128.2, 128.6, 131.2,
132.5, 133.3, 143.6, 156.9, 157.9, 159.7, 160.9; 19F NMR
(deuteriochloroform): ꢀ -60.3.
Anal. Calcd. for C39H47F3N2O2 (632.36) C, 74.02 H, 7.49 N,
4.43. Found C, 73.65 H, 7.63 N, 4.20.
Hz, 2H, HPh), 8.07 (s, 1H, H5), 8.17 (d, J = 7.1 Hz, 2H, HPh); 13
C
6-(4'-Dodecyloxybiphenyl-4-yl)-3-(4-dodecyloxyphenyl)-4-
trifluoromethyl-pyridazine (15).
nmr (deuteriochloroform): ꢀ 14.5, 23.1, 29.8, 29.9, 30.0, 30.1,
31.7, 31.9; 32.4, 36.1, 36.3, 36.4, 120.7, 120.8, 126.1, 128.3,
128.6, 129.8, 130.2, 130.6, 133.4, 133.7, 137.6, 143.5, 144.0,
145.2, 157.3, 158.1; 19F nmr (deuteriochloroform): ꢀ -60.3; ir
(potassium bromide) 808, 842, 1048, 1155, 1182, 1260, 1396,
1467, 1606, 2850, 2918 cm-1.
Cross-coupling reaction of 1 (68 mg, 0.2 mmole) with 4-
dodecyloxyphenylboronic acid (244 mg, 0.8 mmole) according
to the general procedure B (t = 30 hours) gave after purification
by column chromatography (silica, eluent dichloromethane) 123
mg (83%) of 15 as a pale yellow solid, mp 95°. 1H nmr
(deuteriochloroform): ꢀ 0.91 (t, J = 5.6 Hz, 6H, 2xCH3), 1.4
(m, 36H, 18 x CH2), 1.85 (m, 4H, 2 x CH2), 4.06 (m, 4H, 2 x
CH2), 7.06 (m, 4H, HPh), 7.64 (m, 4H, HPh), 7.79 (d, J = 8.7 Hz,
2H, HPh), 8.16 (s, 1H, H5), 8.27 (d, J = 8.2 Hz, 2H, HPh); 13C nmr
(deuteriochloroform): ꢀ 14.5, 23.1, 26.5, 29.7, 29.8, 30.0, 30.1,
32.3, 68.5, 114.7, 115.3, 120.7, 122.7, 127.7, 127.9, 128.2,
128.6, 131.1, 132.5, 133.3, 143.6, 156.9, 157.9, 159.7, 160.9,
161.8; 19F nmr (deuteriochloroform): ꢀ -60.3.
Anal. Calcd. for C47H63F3N2 (713.01) C, 79.17 H, 8.91 N,
3.93. Found C, 78.83 H, 8.62 N, 3.65
6-(4'-(Oct-1-ynyl)biphenyl-4-yl)-3-(4-(oct-1-ynyl)phenyl)-4-tri-
fluoromethyl-pyridazine (13).
Cross-coupling reaction of 1 (60 mg, 0.18 mmole) with 4-oct-
1-ynyl-phenylboronic acid (207 mg, 0.9 mmole) according to
the general procedure B (t = 30 hours) gave after purification by
column chromatography (silica, eluent petroleum ether:
dichloromethane (4:1)) 75 mg (71%) of 13 as a colorless solid,
Anal. Calcd for C47H63F3N2O2 (744.48) C, 75.77 H, 8.52 N,
3.76. Found C, 75.72 H, 8.72 N, 3.73.
1
mp 115-116°. H nmr (deuteriochloroform): ꢀ 0.94 (t, J = 5.4
Hz, 6H, 2 x CH3), 1.47 (m, 16H, 8 x CH2), 2.47 (t, J = 6.8 Hz,
4H, 2 x CH2), 7.54 (m, 8H, HPh), 7.81 (d, J = 8.3 Hz, 2H, HPh),
8.19 (s, 1H, H5) 8.28 (d, J = 8.2 Hz, 2H, HPh); 13C nmr
(deuteriochloroform): ꢀ 13.1, 18.5, 21.6, 27.6, 30.4, 79.1, 79.2,
90.9, 91.6, 122.9, 124.8, 125.8, 126.6, 126.7, 128.1, 130.4,
131.1, 132.6, 133.5, 137.7, 142.0; 19F (deuteriochloroform): ꢀ -
60.3; ir (potassium bromide) 819, 1048, 1086, 1159, 1260, 1404,
2341, 2352, 2856, 2930, 2957cm-1.
4-(Oct-1-ynyl)phenylboronic acid (16).
1-Bromo-4-(oct-1-ynyl)benzene (1.68 g, 6.35 mmoles)
synthesized according to the literature [17] was dissolved in 20
mL of anhydrous THF in a 100 mL flask equiped with a
nitrogen inlet-outlet. The solution was cooled to -78° with a dry
ice-acetone bath. n-Butyllithium (2.5 M in hexane, 3.05 mL, 7.6
mmoles) was added dropwise to the stirring mixture,
maintaining the temperature below -65°. After 30 min,
triisopropylborate (4.39 mL, 19.0 mmoles) was added dropwise.
The temperature was maintained at -78° during 30 min. The
reaction mixture was subsequently warmed to room temperature
and stirred overnight. 10 mL of a mixture THF:HCl:EtOH
(4:1:1) was added then the solution was neutralised with a
saturated sodium hydrogen carbonate solution. The solution
was extracted with diethylether (3 x 10 mL), dried over
magnesium sulfate, filtered and the solvent was evaporared. The
bown powder was washed with dichloromethane to yield 1.46 g
Anal. Calcd. for C39H39F3N2 (592.31) C, 79.03 H, 6.63 N,
4.73. Found C, 79.26 H, 6.36 N, 4.59.
6-(4'-Octyloxybiphenyl-4-yl)-3-(4-octyloxyphenyl)-4-trifluoro-
methylpyridazine (14).
Method 1.
A solution of 1-bromooctane (66 mg, 0.34 mmole, 2.1 equiv.)
in acetone (2 mL) was added to a mixture of 10 (67 mg, 0.16
mmole, 1 equiv.) in acetone (5 mL). The mixture was stirred and
heated under reflux for 48 hours. After cooling at room
temperature acetone was evaporated, then the residue was
extracted with diethyl ether (3x10 mL). The organic phase was
washed with water (5 mL), then with a 5% aqueous sodium
hydroxide solution (5 mL) and finally with water (5 mL), dried
over magnesium sulfate, filtered and evaporated in vacuo. The
crude product was purified by column chromatography (silica
gel, eluent dichloromethane) to give 94 mg (91%) of 14 as a pale
yellow solid.
1
(71%) of a brown solid, mp 118°. H nmr (DMSO-d6): ꢀ 0.88
(m, 3H, CH3), 1.30 (m, 8H, 4 x CH2), 2.43 (t, J = 6.8 Hz, 2H,
CH2), 7.33 (d, J = 7.9 Hz, 2H, HPh), 7.74 (d, J = 7.9 Hz, 2H,
HPh), 8.13 (s, 2H, OH); 13C nmr (DMSO-d6): ꢀ 14.3, 19.0, 22.4,
28.3, 28.4, 31.1, 81.1, 91.9, 125.2, 130.5, 134.5; ir (potassium
bromide) 690, 750, 841, 1179, 1306, 1343, 1401, 1464, 1605,
2857, 2929, 2947 cm-1; MS (EI) m/z 229 (M+, 100).
Method 2.
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(deuteriochloroform): ꢀ 0.92 (m, 6H, 2xCH3), 1.4 (m, 20H,
10xCH2), 1.85 (m, 4H, 4xCH2), 4.05 (m, 4H, 2xOCH2), 7.05 (m,
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(s, 1H, H5), 8.27 (d, J = 8.2 Hz, 2H, HPh); 13C nmr (deuterio-
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