Pd-catalyzed chemoselective cross-coupling reaction of triaryl- or triheteroarylbismuth compounds with 3,6-dihalopyridazines

Article abstract of DOI:10.1002/ejoc.201200977

The cross-coupling reactions of 3,6-dihalopyridazines with triaryl- or triheteroarylbismuth compounds were performed under palladium catalysis. The reaction was highly chemoselective, affording functionalized aryl- or heteroarylpyridazinyl chlorides in moderate to good yields. The cross-coupling reactions of 3,6-dihalopyridazines with triaryl- or triheteroarylbismuth compounds were performed under palladium catalysis. The reaction was highly chemoselective, affording functionalized aryl- or heteroarylpyridazinyl chlorides in moderate to good yields. Copyright

Full text of DOI:10.1002/ejoc.201200977

FULL PAPER
DOI: 10.1002/ejoc.201200977
Pd-Catalyzed Chemoselective Cross-Coupling Reaction of Triaryl- or
Triheteroarylbismuth Compounds with 3,6-Dihalopyridazines
Karène Urgin,[a] Christophe Aubé,[b] Muriel Pipelier,[b] Virginie Blot,[b]
Christine Thobie-Gautier,[b] Stéphane Sengmany,[a] Jacques Lebreton,[b] Eric Léonel,[a]
Didier Dubreuil,[b] and Sylvie Condon*[a]
Keywords: Synthetic methods / Nitrogen heterocycles / Cross-coupling / Arylation / Chemoselectivity / Bismuth / Palladium
The cross-coupling reactions of 3,6-dihalopyridazines with
triaryl- or triheteroarylbismuth compounds were performed
under palladium catalysis. The reaction was highly chemose-
lective, affording functionalized aryl- or heteroarylpyridaz-
inyl chlorides in moderate to good yields.
pyridazines remains a multistep process involving a Pd-cat-
alyzed cross-coupling reaction, starting from 3-chloro-6-
methoxypyridazine and arylboronic acids, followed by
cleavage of the methoxy group with hydroiodic acid and
chlorination of the resulting pyridazinone intermediate with
phosphorus oxychloride.[10] Léonel et al.[11] describe a con-
venient electrochemical reaction to give arylpyridazine de-
rivatives in one step. This straightforward method allows
the coupling of methoxy- or methylpyridazinyl chlorides
with substituted aryl halides under nickel catalysis
(NiBr2bpy) in conjunction with the sacrificial anode pro-
cess.[12] Unfortunately, the reaction conditions could not be
applied to 3,6-dichloropyridazine, as the dihalopyridazinyl
rings either act as coligands or compete with the 2,2Ј-bipyr-
idine (bpy) and poison the nickel catalyst.[13]
Simultaneously, we recently developed a convenient and
versatile method[14] to prepare triarylbismuth compounds
bearing either electron-donating or electron-withdrawing
groups. The process involves BiCl3 and arylzinc reagents,
prepared by a cobalt-catalyzed reaction (see Scheme 1,
Equation 1), and advantageously can be extended to access
heteroarylbismuth compounds {see Scheme 1, Equation 2).
Introduction
Pyridazine derivatives are of considerable importance as
building blocks for various applications in supramolecular
chemistry[1] and as intermediates to afford pyrrole moieties
by ring contraction.[2] Furthermore, compounds containing
a 3,6-disubstituted pyridazinyl ring exhibit extensive bio-
logical activities.[3] In this context, relevant methods are of
considerable importance to facilitate the preparation of new
reactive pyridazine intermediates, which allow access to
challenging dissymmetrical 3,6-disubstituted derivatives
with high biological potentials.[4] Palladium-catalyzed cross-
coupling reactions with pyridazinyl moieties have been pre-
viously explored[5] to produce 6-aryl-substituted 3-chloro-
pyridazines, which are regarded as suitable intermediates
for elaboration to 3,6-diarylpyridazines. A straightforward
method consists of the cross-coupling reaction of 3,6-
dichloropyridazine under Negishi[6] or Suzuki[7] conditions.
However, when using these procedures, mixtures of mono-
and diarylated products are formed in variable ratios.[6–8]
The desymmetrization of 3,6-dichloropyridazine into 3-
chloro-6-iodopyridazine affords better results,[9] but this
procedure has not been extended so far. Until now, the
most efficient way to prepare 6-aryl-substituted 3-chloro-
[a] Equipe d’Electrochimie et Synthèse Organique, Institut de
Chimie et des Matériaux Paris-Est, UMR CNRS 7182,
Université Paris-Est Créteil Val de Marne,
2 Rue Henri Dunant, 94320 Thiais, France
Fax: +33-1-49781148
E-mail: condon@icmpe.cnrs.fr
Homepage: www.icmpe.cnrs.fr
[b] Université de Nantes, CEISAM, Chimie et Interdisciplinarité,
Synthèse, Analyse, Modélisation, UFR des Sciences et des
Techniques, UMR CNRS 6230,
2 Rue de la Houssinière, B. P. 92208, 44322 Nantes Cedex 3,
France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200977.
Scheme 1. Advanced preparation of functionalized triaryl- and
triheteroaryl-bismuth compounds.
Eur. J. Org. Chem. 2013, 117–124
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Condon et al.
FULL PAPER
Because triarylbismuths are of growing interest as atom- 90 °C, in the presence of 10 mol-% Pd(OAc)2 as the catalyst
efficient organometallic reagents in the formation of C–C precursor, PPh3 (40 mol-%) as the ligand, and an excess
bonds[15] and are considered as low or nontoxic,[16] we have amount of CsF (6 equiv.).
explored their behavior in Pd-catalyzed cross-coupling reac-
tions, starting from 3,6-dihalopyridazines.
Under these conditions, the reaction of 1 with 2 afforded
the targeted monoarylated compound 3 in only a moderate
isolated yield (43%) along with 4,4Ј-dimethoxy-1,1Ј-bi-
phenyl (4, 17% by GC). Side product 4 was formed by the
conversion, mediated by Pd catalysis, of tri-p-anisylbismuth
(2) into the corresponding dimeric aryl product.[19,20] The
reaction could be considered as chemoselective, as the for-
mation of 3,6-bis(4-methoxyphenyl)pyridazine, the disubsti-
tuted product, was not observed. Moreover, when the reac-
tion was conducted with an excess amount of 2 (4 equiv.)
versus 1, the formation of 3,6-bis(4-methoxyphenyl)pyrid-
azine was never detected, even by GC analyses. No im-
provement in the yield was observed by the addition of NaI
(1 equiv.).
Finally, the replacement of 1 by 3-chloro-6-iodopyridaz-
ine (5) allowed the formation of the desired compound 3 in
81% isolated yield, and only trace amounts of 4 were de-
tected. Cross-coupling reactions of p-anisylboronic acid
with 1 and with 5 mediated by palladium catalysis were
also performed to compare the reactivity of each of these
organometallic reagents and the chemoselectivity (see
Scheme 4).
Rao et al.[17] recently reported the preparation of unsym-
metrical biphenyls through Pd-catalyzed cross-coupling re-
actions of aryl halides or aryl triflates with triarylbismuths,
bearing mainly electron-donating groups. However, to the
best of our knowledge, the scope of the reaction was limited
to 2-iodopyridine and pyridin-2-yl trifluoromethanesulf-
onate,[16] and very recently to 2-bromo-thiophene and
-benzofurans,[18] as the heteroaryl halide partners. The aim
of this work is to design a general method targeting 3-halo-
6-aryl- and 3-halo-6-heteroarylpyridazines, which are re-
garded as suitable precursors to original dissymmetrical
pyridazines by a chemoselective monosubstitution of one
halogen atom (see Scheme 2).
Scheme 2. Cross-coupling reaction of 3,6-dihalopyridazines and
triaryl- or triheteroarylbismuth compounds.
Again, a better result was obtained, when the halide X
was I rather than Cl. In the two runs, under Suzuki reaction
conditions, a mixture of 3 and diarylated compound 3,6-
bis(4-methoxyphenyl)pyridazine
was
observed
(see
Results and Discussion
Scheme 4, Run 2, 15% yield). However, under different re-
action conditions, Lin and co-workers[7a] reported that a
Suzuki cross-coupling reaction assisted by microwaves gave
monoarylated product 3 in 73% isolated yield, starting
from p-anisylboronic acid and 1. In some cases, the di-
arylated compound was also observed.
To reach our goal, we first studied the cross-coupling
reaction of commercially available 3,6-dichloropyridazine
(1) with tri-p-anisylbismuth (2), according to the standard
reaction conditions described by Rao et al.[16,17] (see
Scheme 3). As previously noted, the three aryl groups on
the bismuth are transferable during the cross-coupling reac-
Then, we examined the change of some parameters, such
tion with the aryl halide.[17] Thus, a slight excess amount of as the amounts of Pd catalyst, CsF, and PPh3, in the model
1 (3.5 equiv.) versus 2 was used, and the reaction was car- reaction involving compounds 5 and 2 (see Scheme 3, X =
ried out under argon in DMF (dimethylformamide) at I; Table 1). Although it was predictable that the reaction
Scheme 3. Preliminary study of the cross-coupling reaction.
Scheme 4. Reaction of 3,6-dihalopyridazine with p-anisylboronic acid.
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Eur. J. Org. Chem. 2013, 117–124

Cross-Coupling Reactions of Triarylbismuth Compounds
did not occur in the absence of the Pd catalyst (see Table 1, ported in the literature.[21,22] It is obvious that the presence
Entry 2), the quantity of the catalyst could be significantly of a base, such as CsF, in the process accelerates the rate of
reduced to 3 mol-% (see Table 1, Entry 3), without altering the cross-coupling reaction, probably by acting on the aryl
either the reaction time (2 h) or the yield (81%).
group transfer from the bismuth to PdII or by promoting
the reductive elimination step, as it has been established in
palladium-catalyzed Suzuki–Miyaura reaction.[23]
We further investigated the cross-coupling reaction of 3-
chloro-6-iodopyridazine (5) with several triarylbismuths,
prepared by our optimized procedure,[14] to examine the
scope and limits of the process. All of the reactions were
first conducted at 90 °C in DMF with 3 mol-% Pd(OAc)2
and 12 mol-% PPh3, but without CsF.
The results are reported in Table 2. As expected, the
cross-coupling reaction occurred efficiently with almost all
of the triarylbismuth compounds, as moderate to high
yields of the corresponding monoarylated compounds were
obtained.
Table 1. Optimization of the cross-coupling reaction.
Entry[a] Pd(OAc)2 PPh3
[mol-%] [mol-%] [equiv.]
CsF
Reaction
time [h]
Isolated
yield [%]
1
2
3
4
5
6
7
10
0
3
3
1
3
3
40
0
12
12
4
0
0
6
6
6
0
0
6
0
2
24
2
3.5
24
3
81
0
81
82
72
50
55
24
[a] Reagents and conditions: Ar3Bi (0.25 mmol) and 3-chloro-6-
iodopyridazine (0.87 mmol) at 90 °C in DMF (3 mL).
The nature and position of the functional groups seem
Various activators such as K3PO4, Cs2CO3, or CsF[15] are to have a strong influence on the course of the reaction. In
usually required as a base to promote reactions involving most cases, better yields were obtained with triphenylbis-
triarylbismuths. Surprisingly, in the absence of CsF, the re- muth and the triarylbismuths bearing electron-donating
action proceeded slower, but still efficiently. The reaction groups in the meta or para position of the aromatic moiety
was completed after only 3.5 h, upon using 3 mol-% (see Table 2, Entries 3, 4, 7, and 8) in comparison to those
Pd(OAc)2 (see Table 1, Entry 4), and the time increased to bearing electron-withdrawing groups. In addition, the yield
24 h when using a lower 1 mol-% Pd(OAc)2 (see Table 1, for the cross-coupling reaction was lower when the electron-
Entry 5). Intriguingly, we also observed that the reaction donating groups were in the ortho position compared to the
could be carried out free of PPh3 (see Table 1, Entry 6), para position of the triarylbismuth reagent, in accordance
despite a decreasing yield, and also free of both PPh3 and with steric hindrance effects (see Table 2, Entries 2–8).
CsF (see Table 1, Entry 7, reaction time 24 h). In the last However, surprisingly, no reaction occurred when an ortho-
two experiments, product 3 was obtained in 50–55% iso- methyl or -ethyl group was positioned on the aryl moiety,
lated yields, along with an increasing formation of 4. On even in the presence of CsF (6 equiv.; see Table 2, Entries 5
the basis of the above results, the mechanism, depicted in and 6). The bismuth reagent and 5 were recovered, along
Scheme 5, is designed to account for Pd catalysis, even in with some trace amounts of 6,6Ј-dichloro-3,3Ј-bipyridazine,
the absence of PPh3. The catalytic reaction is likely initiated detected by GC analyses.
by a transmetallation reaction (see Scheme 5, Step 1) be-
tween Pd(OAc)2 and triarylbismuth, yielding a ArPdAr spe- CO2CH3, CN, COCH3, or CF3, the chemoselective C–C
cies as evidenced by PdII complexes.[21]
couplings performed in only moderate yields that did not
In the presence of electron-withdrawing groups, such as
This intermediate undergoes a reductive elimination (see exceed 47% (see Table 2, Entries 9–16). However, for an un-
Scheme 5, Step 2), leading to biaryl formation and Pd0 that known reason, the cross-coupling reaction efficiently oc-
is likely coordinated to the pyridazinyl moieties. After an curred with F as a substituent (see Table 2, Entry 17).
oxidative addition of 3,6-dihalopyridazine (see Scheme 5, Amazingly, the formation of the biaryl homocoupling side
Step 3), a subsequent transmetallation with triarylbismuth product, from the bismuth reagent, was only observed when
takes place (see Scheme 5, Step 4), followed by a reductive the aryl group was substituted in the ortho position by a
elimination of Pd0 (see Scheme 5, Step 5), as previously re- COCH3 group (see Table 2, Entry 12), and the cross-cou-
Scheme 5. Proposed mechanism for the cross-coupling reaction without PPh3.
Eur. J. Org. Chem. 2013, 117–124
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119

S. Condon et al.
FULL PAPER
Table 2. Synthesis of 6-aryl-substituted 3-chloropyridazines.
seem to strongly depend on the position of the bismuth
atom with respect to the five-membered heteroaromatic
groups (see Table 3, Entries 1–4). Better results were ob-
tained with 3-heteroarylbismuth compounds in comparison
to the 2-substituted reagents (see Table 3, Entries 1–4).
Likewise, the coupling of tris(3-pyridyl)bismuth was ef-
ficient, and the corresponding pyridazine 26 was formed in
48% yield (see Table 3, Entry 5).
Table 3. Synthesis of 6-heteroaryl-substituted 3-chloropyridazines.
Entry[a]
FG
Product
Isolated yield [%]
1
2
3
4
5
6
7
8
–
6
90
43
67
2-OMe
3-OMe
4-OMe
2-Et
2-Me
3-Me
7
8
3
82
9
0 (0)[b]
10
11
12
13
14
15
16
17
18
19
20
21
0 (0)[b]
79
86
47
4-Me
9
2-CO2Me
3-CO2Me
4-CO2Me
2-COCH3
3-COCH3
4-COCH3
4-CN
10
11
12
13
14
15
16
17
39 (59)[b]
30 (58)[b]
0 (0)[b]
32 (53)[b]
34 (55)[b]
25 (37)[b]
45 (54)[b] (50)[c] (53)[d]
80
4-CF3
4-F
[a] Reagents and conditions. (FGAr)3Bi (0.25 mmol, FG = func-
tional group), 5 (3.5 equiv.), solvent is DMF (3 mL), temperature
= 90 °C, Pd(OAc)2 (3%), PPh3 (12%), no base added. [b] Reaction
performed with CsF (6 equiv.). [c] Reaction performed with
Cs2CO3 (6 equiv.). [d] Reaction performed with K2CO3 (6 equiv.).
[a] Reagents and conditions: (HetAr)3Bi (0.25 mmol), 5 (3.5 equiv.),
solvent is DMF (3 mL), T = 90 °C; Pd(OAc)2 (3%), PPh3 (12%),
no base added. [b] Reaction performed with CsF (6 equiv.).
pling reaction proceeded conveniently with CO2CH3 func-
tional group (see Table 1, Entry 9). The transmetallation
step (see Scheme 5, Step 4) may be sensitive to the presence
of an electron-withdrawing group located on the aryl moi-
ety, as observed in most of the tested reagents (see Table 2,
Entries 10–11 and 13–16). The addition of CsF (6 equiv.)
substantially enhanced the yields of the reactions and could
be replaced by Cs2CO3 or K2CO3, without a significant ef-
Conclusions
We have disclosed an efficient, practical, and chemoselec-
fect on the course of the cross-coupling process, as illus- tive method to prepare aryl- and heteroarylpyridazinyl
trated in the reaction involving tris[4-(trifluoromethyl)- chlorides that are versatile synthetic intermediates for the
phenyl]bismuth (see Table 2, Entry 16).
production of a number of dissymmetrical derivatives. This
Until now, only tris(2-thienyl)bismuth[17b,24] has been in- method relies on the peculiar reactivity of the dihalopyrid-
volved in a cross-coupling reaction with organic halides. azines versus triarylbismuths under Pd catalysis, allowing
Given the success of this simple method, we then extended a delicate chemoselective cross-coupling reaction. The best
the scope of the cross-coupling reaction to triheteroarylbis- results were obtained starting from the 3-chloro-6-iodopyr-
muth compounds, prepared by following our procedure,[14] idazine (5). As predicted,[15] the three aryl groups of the
and 3-chloro-6-iodopyridazine (5, see Table 3). The C–C organobismuth reagents were transferable. The addition of
coupling reactions were carried out under the same reaction a base, such as CsF, K2CO3, or Cs2CO3 was beneficial in
conditions as previously used in Table 2. The yields in the the cross-coupling of aryl halides and triarylbismuth com-
monosubstituted pyridazine formation were approximately pounds,[15] but was less important in the reaction involving
from 25 to 64%. In all of the tested reactions involving pyridazinyl halides. However, their influence was mainly ev-
triheteroarylbismuth compounds, a striking and beneficial idenced in the reactions involving triarylbismuth reagents
effect from the addition of CsF was observed (see Table 3, bearing electron-withdrawing group on the transferable aryl
Entries 1–5), which led to a significant increase in the yields moiety, less studied until today, and heteroarylbismuth
of the cross-coupling process (yields 60 to 99%). The yields compounds.
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Cross-Coupling Reactions of Triarylbismuth Compounds
130.9, 127.3, 124.7, 121.5, 111.5, 55.8 ppm. ATR FTIR (neat): ν
˜
max
Experimental Section
= 3079, 2919, 1597, 1567, 1531, 1491, 1460, 1437, 1403, 1298, 1263,
1245, 1181, 1151, 1124, 1089, 1050, 1026, 1000, 874, 855, 836, 784,
751, 692, 572 cm–1. MS (EI): m/z (%) = 221 (5), 219 (16), 202 (6),
191 (5), 186 (13), 185 (100), 184 (6), 168 (5), 167 (16), 157 (21), 140
(5), 131 (14), 127 (5), 130 (9), 115 (8), 107 (5), 103 (7), 102 (17), 63
(9).
General Methods: All of the reactions were carried out under ar-
gon. All reagents and solvents were purchased from commercial
suppliers and used without further purification. Column
chromatography was performed with 35–70 mesh silica gel. Melting
points were determined with a Büchi B545 capillary melting point
apparatus. The 1H, 13C, and 19F NMR spectroscopic data were
recorded with a Bruker Avance II 400 NMR spectrometer, using
irradiation frequencies of 400, 100, and 376 MHz, respectively. The
chemical shifts for the 1H, 13C, and 19F NMR spectra (δ) are given
in part per million (ppm) and referenced internally according to
the residual solvent resonances. Coupling constants were given in
Hertz (Hz), and the abbreviations used are s (singlet), d (doublet), t
(triplet), m (multiplet), dd (double doublet), and dt (double triplet).
Infrared spectra were recorded with a FTIR Bruker Tensor 27 in
ATR (attenuated total reflectance) mode between 5000 and
400 cm–1 with a diamond window. Mass spectra were measured
with a GC–MS apparatus in EI mode [Chromatograph Trace Series
200, equipped with a capillary column CPSIL 5 CB/MS (l = 25 m,
I.D. = 0.25 mm, 0.12 μm)], coupled with a GCQ ThermoFisher
Scientific mass spectrometer. High resolution mass spectrometry
(HRMS in ESI mode) was performed using the mass spectrometry
service of the ICSN (Institut de Chimie et des Substances Natu-
relles), Gif sur Yvette, France. Compounds that have been pre-
viously described in the literature are linked to their corresponding
bibliographic references, whereas compounds labeled by an asterisk
(*) are, to the best of our knowledge, new compounds.
3-Chloro-6-(3-methoxyphenyl)pyridazine[25]
(8):
After
flash
chromatography on silica gel (pentane/EtOAc, 90:10), compound 8
(111 mg, 67% yield) was obtained as a colorless solid; m.p. 95 °C.
1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 9.0 Hz, 1 H), 7.68
(t, J = 2.0 Hz, 1 H), 7.57–7.52 (m, 2 H), 7.42 (t, J = 7.9 Hz, 1 H),
7.06 (dd, J = 7.9 and 2.0 Hz, 1 H), 3.89 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 160.5, 158.6, 155.9, 136.6, 130.3, 128.7,
126.5, 119.5, 116.9, 112.3, 55.7 ppm. ATR FTIR (neat): ν
=
˜
max
2916, 2836, 1607, 1584, 1566, 1537, 1490, 1450, 1434, 1398, 1322,
1268, 1208, 1178, 1151, 1090, 1044, 1015, 900, 885, 836, 785, 761,
689, 666, 565 cm–1. MS (EI): m/z (%) = 222 (19), 221 (39), 220 (58),
219 (100), 207 (9), 192 (7), 191 (17), 190 (20), 132 (8), 103 (6), 102
(21), 63 (9).
3-Chloro-6-(4-methoxyphenyl)pyridazine[7a]
(3):
After
flash
chromatography on silica gel (pentane/EtOAc, 90:10), compound 3
(135 mg, 82% yield) was obtained as a colorless solid, m.p. 160 °C;
1
ref.[7a] m.p. 161–162 °C. H NMR (400 MHz, CDCl3): δ = 8.00 (d,
J = 6.9 Hz, 2 H), 7.77 (d, J = 9.0 Hz, 1 H), 7.50 (d, J = 9.0 Hz, 1
H), 7.02 (d, J = 6.9 Hz, 2 H), 3.87 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 161.8, 158.3, 155.0, 128.7, 128.6, 127.6,
125.7, 114.7, 55.6 ppm. ATR FTIR (neat): νmax = 3050, 3015, 2962,
˜
General Procedure for the Cross-Coupling Reaction between Triaryl-
or Triheteroarylbismuth and 3-Chloro-6-iodopyridazine: A Schlenk
tube containing anhydrous DMF (3 mL) was degassed with argon
for 15 min, and then 3-chloro-6-iodopyridazine 5 (0.87 mmol,
3.5 equiv.), triaryl- or triheteroarylbismuth (0.25 mmol, 1.0 equiv.),
palladium(II) acetate (7.5 μmol, 0.03 equiv.), and triphenylphos-
phane (0.03 mmol, 0.12 equiv.) were sequentially added. The mix-
ture was stirred at 90 °C, until there was total consumption of the
corresponding triaryl- or triheteroarylbismuth compound. After
cooling to room temperature, the mixture was diluted with EtOAc
(5 mL), and the resulting solution was washed with a saturated
solution of NaCl (10 mL) and filtered through a pad of Celite,
which was then rinsed with EtOAc (10 mL). The aqueous phase
was extracted with EtOAc (3ϫ20 mL), dried with Na2SO4, and
filtered, and then the solvents were evaporated under vacuum. The
crude product was purified by flash chromatography on silica gel,
eluting with the appropriate solvents.
2837, 1606, 1581, 1535, 1509, 1454, 1398, 1298, 1256, 1181, 1165,
1150, 1109, 1089, 1026, 1014, 1000, 858, 839, 820, 761, 635, 612,
565 cm–1. MS (EI): m/z (%) = 222 (31), 221 (13), 220 (91), 194 (24),
193 (9), 192 (70), 149 (12), 133 (10), 132 (100), 117 (9), 89 (10), 63
(8).
3-Chloro-6-(3-methylphenyl)pyridazine[26]
(11):
After
flash
chromatography on silica gel (pentane/EtOAc, 90:10), compound
11 (120 mg, 79% yield) was obtained as a colorless solid; m.p.
87 °C. 1H NMR (400 MHz, CDCl3): δ = 7.89 (s, 1 H), 7.82 (d, J =
9.0 Hz, 1 H), 7.80 (d, J = 7.7 Hz, 1 H), 7.55 (d, J = 9.0 Hz, 1 H),
7.41 (t, J = 7.7 Hz, 1 H), 7.33 (d, J = 7.7 Hz, 1 H), 2.45 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.0, 155.7, 139.2,
135.2, 131.5, 129.3, 128.7, 128.0, 126.5, 124.4, 21.7 ppm. ATR
FTIR (neat): ν
= 3084, 3039, 2918, 1950, 1607, 1592, 1567,
˜
max
1535, 1492, 1402, 1376, 1317, 1262, 1192, 1144, 1094, 1038, 917,
887, 858, 835, 784, 761, 692, 671, 620 cm–1. MS (EI): m/z (%) =
206 (31), 205 (12), 204 (100), 178 (12), 176 (36), 141 (25), 116 (69),
115 (91).
3-Chloro-6-phenylpyridazine[9] (6): After flash chromatography on
silica gel (pentane/EtOAc, 90:10), compound 6 (129 mg, 90% yield)
was obtained as a colorless solid, m.p. 145 °C; ref.[9] m.p. 160 °C.
1H NMR (400 MHz, CDCl3): δ = 8.06–8.04 (m, 2 H), 7.84 (d, J =
9.0 Hz, 1 H), 7.57 (d, J = 9.0 Hz, 1 H), 7.55–7.50 (m, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 158.8, 155.8, 135.3, 130.7, 129.4,
3-Chloro-6-(4-methylphenyl)pyridazine[27]
(12):
After
flash
chromatography on silica gel (pentane/EtOAc, 90:10), compound
12 (132 mg, 86% yield) was obtained as a colorless solid, m.p.
1
144 °C; ref.[27] m.p. 151–152 °C. H NMR (400 MHz, CDCl3): δ =
7.94 (d, J = 8.2 Hz, 2 H), 7.80 (d, J = 9.0 Hz, 1 H), 7.53 (d, J =
9.0 Hz, 1 H), 7.33 (d, J = 8.2 Hz, 2 H), 2.43 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 158.7, 155.5, 141.0, 132.5, 130.1,
128.7, 127.3, 126.4 ppm. ATR FTIR (neat): ν
= 3047, 1989,
˜
max
1600, 1570, 1532, 1495, 1447, 1394, 1309, 1259, 1188, 1163, 1143,
1088, 1031, 1007, 919, 854, 777, 740, 688, 564 cm–1. MS (EI): m/z
(%) = 192 (31), 191 (12), 190 (90), 164 (13), 163 (5), 162 (37), 103
(10), 102 (100), 126 (7), 127 (19), 76 (13), 75 (6), 74 (8), 51 (7).
128.6, 127.2, 126.1, 21.6 ppm. ATR FTIR (neat): ν
= 2917,
˜
max
1610, 1571, 1508, 1429, 1396, 1311, 1260, 1192, 1159, 1148, 1087,
1022, 1005, 856, 813, 757, 709, 632, 611, 560 cm–1. MS (EI): m/z
(%) = 206 (31), 205 (13), 204 (95), 178 (13), 177 (5), 176 (38), 141
(16), 139 (6), 117 (8), 116 (82), 115 (100), 89 (13), 63 (5).
3-Chloro-6-(2-methoxyphenyl)pyridazine[7a]
(7):
After
flash
chromatography on silica gel (pentane/EtOAc, 90:10), compound 7
(70 mg, 43% yield) was obtained as a colorless solid; m.p. 122 °C.
1H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 9.0 Hz, 1 H), 7.94
(dd, J = 1.5 and 7.6 Hz, 1 H), 7.49–7.44 (m, 2 H), 7.12 (t, J =
7.6 Hz, 1 H), 7.02 (d, J = 9.0 Hz, 1 H), 3.86 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 158.2, 157.3, 155.1, 131.8, 131.3,
3-Chloro-6-[2-(methoxycarbonyl)phenyl]pyridazine* (13): After flash
chromatography on silica gel (pentane/EtOAc, 70:30), compound
13 (88 mg, 47% yield) was obtained as a colorless solid; m.p.
178 °C. 1H NMR (400 MHz, CDCl3): δ = 8.01 (dd, J = 7.8 and
Eur. J. Org. Chem. 2013, 117–124
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
121

S. Condon et al.
FULL PAPER
1.0 Hz, 1 H), 7.62 (dt, J = 7.8 and 1.0 Hz, 1 H), 7.58–7.53 (m, 4 1358, 1312, 1274, 1261, 1164, 1118, 1093, 1017, 1004, 962, 862,
H), 3.74 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.7,
161.0, 155.9, 137.7, 132.3, 130.8, 130.7, 130.5, 129.8, 129.6, 127.6,
831, 798, 763, 739, 644, 630, 613, 598 cm–1. MS (EI): m/z (%) =
234 (11), 232 (27), 219 (34), 218 (12), 217 (100), 191 (10), 189 (28),
129 (5), 127 (6), 126 (6), 75 (7). HRMS (ESI): calcd. for
C12H10ClN2O [M + H]+ 233.0482; found 233.0493.
52.5 ppm. ATR FTIR (neat): νmax = 3036, 2961, 1722, 1605, 1565,
˜
1533, 1433, 1407, 1328, 1305, 1284, 1239, 1177, 1149, 1111, 1090,
1034, 1026, 1000, 961, 925, 851, 816, 786, 770, 738, 712, 683, 660,
572, 559 cm–1. MS (EI): m/z (%) = 248 (17), 235 (15), 233 (45), 219
(36), 218 (20), 217 (100), 192 (15), 190 (43), 189 (12), 186 (23), 185
(99), 183 (26), 170 (18), 162 (12), 153 (18), 128 (13), 127 (13), 126
(22), 102 (15). HRMS (ESI): calcd. for C12H10ClN2O2 [M + H]+
249.0431; found 249.0440.
3-Chloro-6-(4-cyanophenyl)pyridazine[28]
(19):
After
flash
chromatography on silica gel (pentane/EtOAc, 70:30), compound
19 (60 mg, 37% yield) was obtained as a colorless solid; m.p.
240 °C. 1H NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 8.3 Hz, 2
H), 7.88 (d, J = 9.0 Hz, 1 H), 7.84 (d, J = 8.3 Hz, 2 H), 7.65 (d, J
= 9.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.0,
156.8, 139.5, 133.1, 129.0, 127.9, 126.4, 118.4, 114.5 ppm. ATR
3-Chloro-6-[3-(methoxycarbonyl)phenyl]pyridazine* (14): After flash
chromatography on silica gel (pentane/EtOAc, 70:30), compound
14 (109 mg, 59% yield) was obtained as a colorless solid; m.p.
FTIR (neat): ν
= 3746, 3040, 2921, 2852, 2224, 1730, 1566,
˜
max
1531, 1460, 1404, 1365, 1261, 1193, 1151, 1091, 1018, 856, 828,
796, 785, 763, 749, 691, 653, 564 cm–1. MS (EI): m/z (%) = 217
(28), 216 (13), 215 (89), 189 (13), 188 (6), 187 (45), 152 (13), 128
(10), 127 (100), 125 (5), 100 (9), 75 (9), 74 (15).
3-Chloro-6-[4-(trifluoromethyl)phenyl]pyridazine[29] (20): After flash
chromatography on silica gel (pentane/EtOAc, 70:30), compound
20 (105 mg, 54% yield) was obtained as a colorless solid; m.p.
181 °C. 1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 8.2 Hz, 1
H), 7.88 (d, J = 9.0 Hz, 2 H), 7.80 (d, J = 8.2 Hz, 2 H), 7.63 (d, J
= 9.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 157.5,
156.6, 138.6, 137.9, 132.7, 128.9, 127.7 (q, J = 32 Hz), 126.5 (q, J
= 272 Hz), 126.3 (q, J = 4 Hz) ppm. 19F NMR (376 MHz, CDCl3):
1
140 °C. H NMR (400 MHz, CDCl3): δ = 8.63 (s, 1 H), 8.34 (dd,
J = 7.8 and 1.0 Hz, 1 H), 8.17 (d, J = 7.8 Hz, 1 H), 7.91 (d, J =
8.9 Hz, 1 H), 7.63 (t, J = 7.8 Hz, 1 H), 7.61 (d, J = 8.9 Hz, 1 H),
3.96 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.7, 157.9,
156.2, 135.6, 131.7, 131.6, 131.3, 129.6, 128.9, 128.2, 126.4,
52.6 ppm. ATR FTIR (neat): νmax = 3036, 2961, 1722, 1605, 1565,
˜
1533, 1433, 1407, 1328, 1305, 1284, 1239, 1177, 1149, 1111, 1090,
1034, 1026, 1000, 961, 925, 851, 816, 786, 770, 738, 712, 683, 660,
572 cm–1. MS (EI): m/z (%) = 250 (10), 248 (39), 217 (21), 192 (36),
191 (18), 190 (100), 189 (20), 129 (30), 101 (13), 75 (12). HRMS
(ESI): calcd. for C12H10ClN2O2 [M + H]+ 249.0431; found
249.0432.
δ = –62.7 ppm. ATR FTIR (neat): ν
= 3037, 1615, 1536, 1417,
˜
max
1402, 1323, 1260, 1161, 1108, 1067, 1016, 1005, 835, 798, 763, 739,
687, 600 cm–1. MS (EI): m/z (%) = 261 (5), 260 (34), 259 (13), 258
(100), 239 (7), 232 (19), 231 (6), 230 (52), 195 (11), 180 (5), 175 (6),
171 (9), 170 (92), 169 (19), 151 (12), 120 (14), 75 (6).
3-Chloro-6-[4-(methoxycarbonyl)phenyl]pyridazine* (15): After flash
chromatography on silica gel (pentane/EtOAc, 70:30), compound
15 (108 mg, 58% yield) was obtained as a colorless solid; m.p.
206 °C. 1H NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 8.5 Hz, 2
H), 8.12 (d, J = 8.5 Hz, 2 H), 7.88 (d, J = 9.0 Hz, 1 H), 7.61 (d, J
= 9.0 Hz, 1 H), 3.96 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 166.7, 157.8, 156.4, 139.3, 132.0, 130.5, 128.8, 127.3, 126.6,
3-Chloro-6-(4-fluorophenyl)pyridazine[25]
(21):
After
flash
chromatography on silica gel (pentane/EtOAc, 80:20), compound
21 (125 mg, 80% yield) was obtained as a colorless solid; m.p.
157 °C. 1H NMR (400 MHz, CDCl3): δ = 8.07–8.02 (m, 2 H), 7.80
(d, J = 9.0 Hz, 1 H), 7.57 (d, J = 9.0 Hz, 1 H), 7.24–7.18 (m, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.5 (d, J = 251 Hz),
157.8, 155.8, 131.4 (q, J = 3 Hz), 129.3, 128.8, 126.1, 116.5 (d, J =
22 Hz) ppm. 19F NMR (376 MHz, CDCl3): δ = –110.1 ppm. ATR
52.6 ppm. ATR FTIR (neat): νmax = 2962, 1725, 1610, 1577, 1530,
˜
1430, 1414, 1397, 1296, 1278, 1195, 1152, 1113, 1021, 1006, 957,
877, 837, 776, 748, 731, 694, 611, 559 cm–1. MS (EI): m/z (%) =
250 (31), 249 (13), 248 (93), 220 (17), 217 (100), 189 (21), 160 (13),
129 (28), 126 (11), 75 (11). HRMS (ESI): calcd. for C12H10ClN2O2
[M + H]+ 249.0431; found 249.0429.
FTIR (neat): ν
= 3054, 1600, 1568, 1504, 1417, 1395, 1302,
˜
max
1287, 1239, 1164, 1150, 1090, 1015, 863, 832, 764, 613, 560 cm–1.
MS (EI): m/z (%) = 210 (30), 209 (12), 208 (95), 182 (22), 181 (7),
180 (63), 145 (11), 121 (9), 120 (100), 100 (6), 75 (10), 74 (14).
6-(3-Acetylphenyl)-3-chloropyridazine* (17): After flash chromatog-
raphy on silica gel (pentane/EtOAc, 50:50), compound 17 (93 mg,
53% yield) was obtained as a colorless solid; m.p. 133 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.62 (s, 1 H), 8.32 (d, J = 7.7 Hz, 1 H),
8.11 (d, J = 7.7 Hz, 1 H), 7.92 (d, J = 9.0 Hz, 1 H), 7.66 (t, J =
7.7 Hz, 1 H), 7.62 (d, J = 9.0 Hz, 1 H), 2.69 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 197.7, 157.9, 156.3, 138.1, 135.9,
131.7, 130.4, 129.8, 128.9, 127.0, 126.4, 27.0 ppm. ATR FTIR
3-Chloro-6-(2-thienyl)pyridazine[9] (22): After flash chromatography
on silica gel (pentane/EtOAc, 70:30), compound 22 (146 mg, 99%
yield) was obtained as a colorless solid, m.p. 151 °C; ref.[9] m.p.
160–162 °C. 1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 9.0 Hz,
1 H), 7.66 (dd, J = 3.7 and 1.1 Hz, 1 H), 7.52 (dd, J = 5.0 and
1.1 Hz, 1 H), 7.49 (d, J = 9.0 Hz, 1 H), 7.17 (dd, J = 5.0 and
3.7 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 155.0, 154.5,
139.5, 130.2, 128.6, 128.5, 127.2, 124.7 ppm. ATR FTIR (neat):
(neat): νmax = 3056, 2925, 1680, 1601, 1568, 1535, 1436, 1403, 1356,
˜
1300, 1272, 1225, 1193, 1172, 1153, 1098, 1038, 1021, 963, 927,
904, 852, 839, 815, 793, 747, 678, 666, 630, 589 cm–1. MS (EI): m/z
(%) = 234 (25), 233 (9), 232 (74), 219 (33), 218 (15), 217 (100), 204
(17), 191 (17), 190 (11), 189 (50), 129 (8), 127 (8), 126 (6), 101 (7),
75 (7). HRMS (ESI): calcd. for C12H10ClN2O [M + H]+ 233.0482;
found 233.0477.
ν
max = 3059, 1568, 1535, 1433, 1399, 1356, 1327, 1267, 1156, 1074,
˜
1057, 963, 853, 835, 763, 710, 586 cm–1. MS (EI): m/z (%) = 198
(35), 197 (11), 196 (100), 170 (11), 168 (33), 133 (22), 109 (8), 108
(86), 89 (8), 82 (11), 74 (7), 69 (10), 63 (8), 58 (8).
6-(4-Acetylphenyl)-3-chloropyridazine (18):* After flash chromatog-
raphy on silica gel (pentane/EtOAc, 70:30), compound 18 (96 mg,
55% yield) was obtained as a colorless solid; m.p. 205 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.17 (d, J = 8.7 Hz, 2 H), 8.11 (d, J =
3-Chloro-6-(3-thienyl)pyridazine[26] (23): After flash chromatog-
raphy on silica gel (pentane/EtOAc, 70:30), compound 23 (133 mg,
90% yield) was obtained as a colorless solid; m.p. 159 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.03 (dd, J = 3.0 and 1.3 Hz, 1 H), 7.75
8.7 Hz, 2 H), 7.89 (d, J = 8.9 Hz, 1 H), 7.63 (d, J = 8.9 Hz, 1 H), (dd, J = 5.1 and 1.3 Hz, 1 H), 7.72 (d, J = 8.9 Hz, 1 H), 7.51 (d, J
2.67 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 197.7, 157.8, = 8.9 Hz, 1 H), 7.46 (dd, J = 5.1 and 3.0 Hz, 1 H) ppm. 13C NMR
156.4, 139.4, 138.5, 129.3, 128.9, 127.5, 126.6, 27.0 ppm. ATR
FTIR (neat): ν = 3060, 1672, 1606, 1572, 1531, 1413, 1394,
(100 MHz, CDCl3): δ = 155.0, 154.9, 137.6, 128.7, 127.5, 126.2,
126.1, 125.8 ppm. ATR FTIR (neat): ν = 3077, 3041, 1572,
˜
˜
max
max
122
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 117–124

Cross-Coupling Reactions of Triarylbismuth Compounds
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Schmidt, C. T. Helaszek, M. A. Ator, Bioorg. Med. Chem. Lett.
1997, 7, 1003–1006; b) M. F. Braña, M. Cacho, M. L. García,
E. P. Mayoral, B. López, B. Pascual-Teresa, A. Ramos, N.
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1532, 1430, 1388, 1299, 1255, 1215, 1153, 1097, 1026, 894, 860,
849, 806, 783, 747, 703, 633 cm–1. MS (EI): m/z (%) = 199 (35),
198 (11), 197 (100), 171 (11), 169 (29), 133 (16), 108 (60).
3-Chloro-6-(2-furyl)pyridazine* (24): After flash chromatography
on silica gel (pentane/EtOAc, 70:30), compound 24 (100 mg, 74%
yield) was obtained as a colorless solid; m.p. 102 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.80 (d, J = 9.0 Hz, 1 H), 7.62 (d, J =
1.8 Hz, 1 H), 7.51 (d, J = 9.0 Hz, 1 H), 7.36 (d, J = 3.4 Hz, 1 H),
6.60 (dd, J = 3.4 and 1.8 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 154.8, 151.6, 150.0, 145.1, 128.5, 124.2, 113.0,
[3]
[4]
[5]
111.4 ppm. ATR FTIR (neat): νmax = 3114, 3076, 2923, 2853, 2360,
˜
1600, 1565, 1525, 1479, 1412, 1376, 1286, 1218, 1162, 1142, 1106,
1068, 1036, 1001, 904, 883, 835, 762, 661, 596 cm–1. MS (EI): m/z
(%) = 182 (32), 181 (10), 180 (100), 154 (11), 152 (36), 93 (5), 92
(61), 89 (13), 64 (17), 63 (32), 62 (8). HRMS (ESI): calcd. for
C8H6N2OCl [M + H]+ 181.0169; found 181.0172.
3-Chloro-6-(3-furyl)pyridazine* (25): After flash chromatography
on silica gel (pentane/EtOAc, 70:30), compound 25 (130 mg, 96%
yield) was obtained as a colorless solid; m.p. 169 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.14 (s, 1 H), 7.57 (m, 2 H), 7.49 (d, J =
9.0 Hz, 1 H), 7.01 (d, J = 1.8 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 155.0, 153.7, 144.8, 142.5, 128.5, 125.8, 123.4,
108.6 ppm. ATR FTIR (neat): νmax = 3132, 3094, 3040, 2922, 1985,
˜
1703, 1616, 1592, 1567, 1535, 1509, 1413, 1392, 1326, 1261, 1154,
1114, 1070, 1045, 1010, 923, 875, 847, 819, 762, 735, 641, 590 cm–1.
MS (EI): m/z (%) = 182 (31), 181 (10), 180 (100), 154 (8), 152 (24),
92 (52), 89 (23), 64 (11), 63 (29), 62 (9). HRMS (ESI): calcd. for
C8H6N2OCl [M + H]+ 181.0169; found 181.0175.
3-Chloro-6-(3-pyridyl)pyridazine[7a] (26): After flash chromatog-
raphy on silica gel (pentane/EtOAc, 50:50), compound 26 (86 mg,
60% yield) was obtained as a colorless solid; m.p. 155 °C. 1H NMR
(400 MHz, CDCl3): δ = 9.20 (s, 1 H), 8.76 (dd, J = 7.7 and 1.7 Hz,
1 H), 8.45 (t, J = 7.7 Hz, 1 H), 7.89 (d, J = 9.0 Hz, 1 H), 7.64 (d,
J = 9.0 Hz, 1 H), 7.49 (dd, J = 7.7 and 1.7 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 156.6, 156.5, 151.7, 148.3, 134.8,
[6]
[7]
D. S. Chekmarev, A. E. Stepanov, A. N. Kasatkin, Tetrahedron
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[8]
[9]
[10]
[11]
I. Parrot, Y. Rival, C.-G. Wermuth, Synthesis 1999, 7, 1163–
131.2, 129.0, 126.2, 124.2 ppm. ATR FTIR (neat): ν
= 3044,
˜
max
1168.
1590, 1566, 1534, 1481, 1431, 1394, 1359, 1320, 1265, 1193, 1173,
1152, 1121, 1101, 1048, 1023, 1001, 864, 808, 794, 757, 700, 638,
620, 572 cm–1. MS (EI): m/z (%) = 192 (34), 191 (13), 190 (100),
164 (11), 163 (33), 128 (18), 104 (6), 103 (53), 101 (6), 76 (31), 75
(12), 74 (13), 51 (6), 50 (6).
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[12]
[13]
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra for all compounds
are detailed.
[14]
[15]
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We gratefully acknowledge financial support by the Agence Na-
tionale de la Recherche (ANR) (Program Foldapsules and a Ph.D.
grant to C. A.) and by the Centre National de la Recherche Sci-
entifique (CNRS). K. U. thanks the Université Paris-Est Créteil,
Val de Marne (UPEC), and Ministère de l’Enseignement Supérieur
et de la Recherche for a Ph.D. grant. The authors also thank La
Ligue Contre le Cancer for financial support.
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