Preparation of functionalized aryl- and heteroarylpyridazines by nickel-catalyzed electrochemical cross-coupling reactions

Article abstract of DOI:10.1021/jo070429+

(Chemical Equation Presented) A general efficient electrochemical method for the preparation of aryl- and heteroarylpyridazines in a nickel-catalyzed cross-coupling reaction of 3-chloro-6-methoxypyridazine and 3-chloro-6- methylpyridazine with a range of functionalized aryl or heteroaryl halides is reported.

Full text of DOI:10.1021/jo070429+

Preparation of Functionalized Aryl- and Heteroarylpyridazines by
Nickel-Catalyzed Electrochemical Cross-Coupling Reactions
Ste´phane Sengmany,† Eric Le´onel,*,† Frantz Polissaint,† Jean-Yves Ne´de´lec,†
Muriel Pipelier,‡ Christine Thobie-Gautier,§ and Didier Dubreuil‡
Electrochimie et Synthe`se Organique, Institut de Chimie et des Mate´riaux Paris-Est UMR 7182-CNRS,
UniVersite´ Paris 12, 2 rue Henri-Dunant, F-94320 Thiais, France, Laboratoire de Synthe`se Organique,
UMR 6513-CNRS, UniVersite´ de Nantes, 2 rue de la Houssinie`re, BP 92208, F-44322 Nantes Cedex 3,
France, and Laboratoire d’Analyse Isotopique et Electrochimique de Me´tabolismes, UMR 6006-CNRS,
UniVersite´ de Nantes, 2 rue de la Houssinie`re, BP 92208, F-44322 Nantes Cedex 3, France
leonel@glVt-cnrs.fr
ReceiVed March 13, 2007
A general efficient electrochemical method for the preparation of aryl- and heteroarylpyridazines in a
nickel-catalyzed cross-coupling reaction of 3-chloro-6-methoxypyridazine and 3-chloro-6-methylpyridazine
with a range of functionalized aryl or heteroaryl halides is reported.
Introduction
methods.4 Pyrrole components are widely found in natural
products and in many pharmaceuticals.5 In addition to the many
biological applications reported in the literature, pyridazine
moiety also plays an important role as chelating agent or metal
complexing ligand. Indeed, associated with heteroaryl rings, e.g.,
pyridines, the pyridazine ring can be employed for constructing
grid-like architectures through self-assembly processes with
metal ions like Cu(I) and Ag(I).6,7
Substituted arylpyridazines have given rise to considerable
interest because of their diverse pharmacological properties
ranging from antibacterial and antifungal to anti-inflammatory,
antidepressant, and cardiovascular drugs (Figure 1).1
Pyridazine rings can also be used as precursors of pyrroles
by ring contraction2 by either chemical3 or electrochemical
* Author to whom correspondence should be addressed. Phone: +33-1-49-
78-11-36. Fax: +33-1-49-78-11-48.
Numerous publications have dealt with the preparation of
substituted pyridazines by conventional chemical routes. Basi-
cally, the approach involves a transition metal mediated carbon-
carbon bond forming cross-coupling, mainly through palladium
or nickel complex catalysis, and usually referred to as Kumada,8
† Universite´ Paris 12.
‡ Laboratoire de Synthe`se Organique, Universite´ de Nantes.
§ Laboratoire d’Analyse Isotopique et Electrochimique de Me´tabolisme,
Universite´ de Nantes.
(1) (a) Heinisch, G.; Kopelent-Frank, H. Progress in Medicinal Chem-
istry: Pharmacologically ActiVe Pyridazine DeriVatiVes, Part 2; Ellis G.P.,
Luscombe D.K., Eds; Elsevier Science B.V.; Amsterdam, The Netherlands,
1992; Vol. 29, pp 141-183. (b) So¨nmez, M.; Berber, I.; Akbas, E. Eur J.
Med. Chem. 2006, 41, 101-105. (c) Rohet, F.; Rubat, C.; Coudert, P.;
Couquelet, J. Bioorg. Med. Chem. 1997, 5, 655-659. (d) Dolle, R. E.;
Hoyer, D.; Rinker, J. M.; Ross, T. M.; Schmidt, S. J.; Helaszek, C. T.;
Ator, M. A. Bioorg. Med. Chem. Lett. 1997, 7, 1003-1006. (e) Steiner,
G.; Gries, J.; Lenke, D. J. Med. Chem. 1981, 24, 59-68. (f) Sotelo, E.;
Fraiz, N.; Yanez, M.; Terrades, V.; Laguna, R.; Cano, E.; Ravina, E. Bioorg.
Med. Chem. 2002, 10, 2873-2882.
(4) Manh, G. T.; Hazard, R.; Tallec, A.; Prade`re, J. P.; Dubreuil, D.;
Thiam, M.; Toupet, L. Electrochim. Acta 2002, 47, 2833-2841.
(5) (a) Joshi, U.; Josse, S.; Pipelier, M.; Chevallier, F.; Prade`re, J. P.;
Hazard, R.; Legoupy, S.; Huet, F.; Dubreuil, D. Tetrahedron Lett. 2004,
45, 1031-1033. (b) Sternberg, E. D.; Dolphin, D.; Bru¨ckner, C. Tetrahedron
1998, 54, 4151-4202. (c) Fu¨rstner, A. Angew. Chem., Int. Ed. 2003, 42,
3582-3603.
(6) Hoogenboom, R.; Kickelbick, G.; Schubert, U. S. Eur. J. Org. Chem.
2003, 4887-4896.
(2) Joshi, U.; Pipelier, M.; Naud, S.; Dubreuil, D. Curr. Org. Chem.
2005, 9, 261-288.
(3) Boger, D. L.; Coleman, R. S.; Ponek, J. S.; Yohannes, D. J. Org.
Chem. 1984, 49, 4405-4409.
(7) Baxter, P. N. W.; Lehn, J.-M.; Baum, G.; Fenske, D. Chem. Eur. J.
2000, 6, 4510-4517.
(8) Corbet, J.-P.; Magnani, G. Chem. ReV. 2006, 106, 2651-2710.
10.1021/jo070429+ CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/20/2007
J. Org. Chem. 2007, 72, 5631-5636
5631

Sengmany et al.
FIGURE 1. Examples of arylpyridazine derivatives and their properties.
or Negishi,9 Stille,10 or Suzuki11 reaction. For instance, Rival
et al.12 have synthesized a series of substituted arylpyridazines
in 50% to 90% yields by a Suzuki reaction from 3-chloro-6-
methoxypyridazine and substituted phenylboronic acids in
toluene/ethanol medium at 110 °C in the presence of tetrakis-
(triphenylphosphine)palladium and sodium carbonate. Another
example reported by Bailey et al.13 is the coupling of iodopy-
ridazine with heteroarylstannanes according to the Stille pro-
cedure. The drawback of these two methods is the need of
preparing reagents like phenylboronic acids or heteroarylstan-
nanes, which can hardly be obtainable if the aryl ring bears
sensitive functional groups. Alternative approaches have also
been reported. Thus, Krische and co-workers14 have described
the rhodium-catalyzed aldolization of enals with glyoxal fol-
lowed by treatment with hydrazine to afford 3-arylpyridazines
in moderate yields. Sauer et al.15 have prepared 3-aryl and
3-heteroaryl-5-stannylated pyridazines by a [4+2] cycloaddition
of 3-aryl or 3-heteroaryl-1,2,4,5-tetrazines with ethynyltributyltin
in high yields.
To our knowledge, there has been no reports concerning the
use of an electrochemical approach to perform of such cross-
coupling. In our laboratory, Gosmini16 has previously described
the preparation in good yields of several arylpyridines, aryl-
pyrimidines, and arylpyrazines by nickel bromide 2,2′-bipyridine
complex (NiBr2bpy) catalysis combined with an electroreductive
process.17
In this paper we report the application of this simple and
smooth one-pot nickel-catalyzed electrochemical method to
access a library of various functionalized aryl- or heteroaryl-
pyridazines. We particularly turned our attention to the cross-
coupling reaction of 3-chloro-6-methoxypyridazine and 3-chloro-
6-methylpyridazine, with a range of aryl or heteroaryl halides
variously substituted by electron-withdrawing and electron-
donating functional groups. We have an interest to these two
6-methoxy- and 6-methyl-substituted chloropyridazines not only
because of their cost and their limited commercially availability,
but especially because of their possible further synthetic
transformations. For instance, the methoxy group of resulting
cross-coupled product, once hydrolyzed, can be halogenated and
then subjected to a second cross-coupling reaction. On the other
hand, the methyl group can be used to introduce a functional
group like a carboxylic acid after oxidation.
Results and Discussion
We started by investigating the cross-coupling reaction
between 3-chloro-6-methoxypyridazine and methyl 4-bromoben-
zoate (Scheme 1). This latter substrate has been taken as a model
because of its efficient nickel-catalyzed homocoupling. After
having tuned the key reaction parameters such as the nature of
the catalyst (NiBr2 or CoCl2 in DMF/pyridine, NiBr2(PPh3)2 or
NiBr2bpy in DMF), anode (Fe/Ni: 64/36, Fe, Mg, Zn), and
current density (0.05, 0.1, 0.2 A), we found the following as
the most convenient and general set of reaction conditions: the
reaction is conducted in DMF, at a constant current of 0.2 A,
and with an iron rod as the anode, 10% of NiBr2bpy as the
catalyst, and a stoichiometric amount of the two reagents. The
reactions went to completion in 3 to 4 h. The other conditions
afforded no more than 20% GC of the cross-coupled product,
homocoupled or reduction products were the major products.
Under the optimized working reaction conditions, methyl 4-(6-
methoxypyridazin-3-yl)-benzoate (3a) was obtained in 57%
yield.
This satisfactory first result opened the way for a screening
of cross-coupling between a broad range of aromatic and
heteroaromatic halides and 3-chloro-6-methoxypyridazine or
3-chloro-6-methylpyridazine. The reaction conditions were
similar those used for the model reaction above. The results
are given in Tables 1-3.
Table 1 deals with the results obtained with electron-
withdrawing (EWG) substituted phenyl halides. The influence
of both the position of the EWG and the nature of the halogen
atom (X) on the yield of the cross-coupling products (com-
pounds 1-13 in Table 1) is noticeable.
In the absence of a substituent on the phenyl ring, iodine is
required for the cross-coupling reaction, while bromine is
suitable for EWG-substituted phenyl halides, as long as the
substituent is not ortho to the halogen in the case of 3-chloro-
6-methoxypyridazine. Indeed, only traces of cross-coupled
products 1-12 were formed from 2-substituted bromobenzenes
with either 3-chloro-6-methoxypyridazine or 3-chloro-6-meth-
(9) Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42, 1821-
1823.
(10) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524.
(11) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(12) Parrot, I.; Rival, Y.; Wermuth, C. G. Synthesis 1999, 7, 1163-
1168.
(13) Draper, T. L.; Bailey, T. R. J. Org. Chem. 1995, 60, 748-750.
(14) Marriner, G. A.; Garner, S. A.; Jang, H-Y.; Krische, M. J. J. Org.
Chem. 2004, 69, 1380-1382.
(15) Sauer, J.; Heldmann, D. K. Tetrahedron 1998, 54, 4297-4312.
(16) (a) Gosmini, C.; Lasry, S.; Ne´de´lec, J.-Y.; Pe´richon, J. Tetrahedron
1998, 54, 1289-1298. (b) Gosmini, C.; Ne´de´lec, J.-Y.; Pe´richon, J.
Tetrahedron Lett. 2000, 41, 201-203.
(17) Chaussard, J.; Folest, J.-C.; Ne´de´lec, J.-Y.; Pe´richon, J.; Sibille, S.;
Troupel, M. Synthesis 1990, 5, 369-381.
5632 J. Org. Chem., Vol. 72, No. 15, 2007

Preparation of Aryl- and Heteroarylpyridazines
SCHEME 1. Preparation of Methyl 4-(6-Methoxypyridazin-3-yl)benzoate (3a)
ylpyridazine (entries 1, 4, 7, and 10, Table 1); the reactions led
instead exclusively to the reduction of the phenyl halide and
formation of a small amount of pyridazine dimer. EWG-4-
substituted bromobenzenes gave the cross-coupling products in
satisfactory average 60% yield (entries 3, 6, 9, and 12, Table
1). Iodine instead of bromine seems to impede somehow the
cross-coupling reaction as illustrated with 4-haloacetophenone
(entries 12 and 14, Table 1), while chloro derivatives are not
reactive at all. In the case of EWG-3-substituted bromobenzenes,
yields of the cross-coupled products with 3-chloro-6-methoxy-
pyridazine were surprisingly lower (18-50%, entries 2, 5, 8,
and 11, Table 1) than those with the para-substituted derivatives;
the identified side products were the two dimers.
Since 3-substituted phenyl halides gave low to moderate
yields, we tried to improve them by doubling the amount of
the phenyl halides (10 mmol) relative to 3-chloro-6-methoxy-
pyridazine (5 mmol). In all cases, yields are significantly
increased, ranging from 57% to 99% (entries 2, 5, 8, and 11,
numbers in parentheses, Table 1). Applying this modified
procedure with a 4-substituted phenyl halide (4-bromobenzoni-
trile) showed also a slight improvement of the yield, from 58%
to 68% (entry 6, Table 1). However, this procedure could not
allow cross-coupling of EWG-ortho-substituted phenyl halides
with pyridazine halides (entry 1, Table 1).
yields which are, however, lower than those for the correspond-
ing methoxypyridazine. In addition, 3- and 2-substituted bro-
mobenzenes only gave traces of the cross-coupled products,
except 3-bromobenzonitrile. The same side products were
detected as previously observed. By increasing the amount of
3-bromobenzonitrile we could only obtain a 31% moderate yield
of the cross-coupling product (entry 5, Table 1).
We next explored this cross-coupling reaction between
electron-donating group (EDG)-substituted phenyl halides and
the two pyridazines. The results are collected in Table 2.
The two EDGs studied were methyl and methoxy attached
at various positions relative to the halogen, which is either
bromine or iodine. It comes out that no cross-coupling was
obtained from the bromo compounds (entries 1, 2, 3, and 7,
Table 2), and the dimer of the pyridazine was formed. Switching
to the iodo derivatives enabled the formation of the cross-
coupling product in good yields (entries 4-6 and 8-10,
Table 2).
We then focused our attention on the effect of a fluorine atom
substituent on the phenyl ring (Table 3).
Surprisingly, the behavior of fluorine derivatives seemed to
follow the electron-donating group trend. The cross-coupling
reaction with 3-chloro-6-methoxypyridazine and 3-chloro-6-
methylpyridazine only occurred with the aryl iodides (entries
3, 4, and 5, Table 3), though in yields lower than those from
EDGs, and the corresponding 3- and 4-fluoro phenyl bromide
did not react (entries 1 and 2, Table 3).
Finally, we completed the screening by engaging heteroaryl
halides in the electrochemical cross-coupling with 3-chloro-6-
methoxypyridazine (Table 4).
Bromide derivatives in the heteroaryl gave the best result
yielding 64% of the cross-coupled product 23a (entry 1, Table
4). Iodide derivative led to a 22% yield of the product,
accompanied by the reduced pyridine product, and the homo-
coupled 2,2′-bipyridine and bipyridazinic products. No cross-
The behavior of 3-chloro-6-methylpyridazine in the coupling
with EWG-substituted phenyl halides was surprisingly found
to be rather different from that observed with the 6-methoxylated
derivative. Indeed, only 4-substituted bromobenzenes underwent
the cross-coupling reaction (entries 3, 6, 9, and 12, Table 1) in
TABLE 1. Cross-Coupling Reaction between
3-Chloro-6-methoxypyridazine or 3-Chloro-6-methylpyridazine and
EWG-Substituted Phenyl Halides
TABLE 2. Cross-Coupling Reaction between
3-Chloro-6-methoxypyridazine or 3-Chloro-6-methylpyridazine and
EDG-Substituted Phenyl Halides
R ) OCH3 isolated
R ) CH3
isolated
entry
FG
X
products a yields (%) products b yields (%)
a
1
2
3
4
5
6
7
8
9
2-CO2CH3 Br
3-CO2CH3 Br
4-CO2CH3 Br
2-CN
3-CN
4-CN
2-CF3
3-CF3
4-CF3
1a
2a
3a
4a
5a
6a
7a
8a
-a (-a)b
45 (86)b
57
1b
2b
3b
4b
5b
6b
7b
8b
-
-
a
59
a
a
Br
Br
Br
Br
Br
Br
-
-
27 (99)b
58 (68)b
12 (31)b
46
R ) OCH3
isolated
R ) CH3
isolated
a
a
-
-
-
entry
FG
X
product a yields (%) product b yields (%)
50 (67)b
62
a
a
a
a
a
a
a
9a
9b
18
1
2
3
4
5
6
7
8
9
2-CH3
3-CH3
4-CH3
2-CH3
3-CH3
4-CH3
Br
Br
Br
I
I
I
14a
15a
16a
14a
15a
16a
17a
18a
19a
17a
-
-
-
14b
15b
16b
14b
15b
16b
17b
18b
19b
17b
-
-
-
a
a
10 2-COCH3 Br
11 3-COCH3 Br
12 4-COCH3 Br
13 4-COCH3 Cl
10a
11a
12a
12a
12a
13a
13a
13a
-
10b
11b
12b
12b
12b
13b
13b
13b
-
-
18 (57)b
50
a
30
73
71
56
47
73
53
a
a
-
-
14 4-COCH3
I
18
21
a
a
a
a
15
16
17
H
H
H
Cl
Br
I
-
-
-
-
4-OCH3 Br
-
-
a
a
2-OCH3
3-OCH3
4-OCH3
I
I
I
50
56
44
55
60
75
60
53
10
a The reaction led either exclusively to the reduction products or to the
mixture of the reduction, dimers and cross-coupled products (<10% GC).
b 3-Chloro-6-methoxypyridazine or 3-chloro-6-methylpyridazine (5mmol)/
aromatic halides (10 mmol).
a The reaction led either exclusively to the reduction products or to the
mixture of the reduction, dimers and cross-coupled products (<10%
GC).
J. Org. Chem, Vol. 72, No. 15, 2007 5633

Sengmany et al.
SCHEME 2. Proposed Catalytic Cycle for the
TABLE 3. Cross-Coupling Reaction between
3-Chloro-6-methoxypyridazine or 3-Chloro-6-methylpyridazine and
Fluoro-Substituted Phenyl Halides
Cross-Coupling Reactions
R ) OCH3
product a
isolated
R ) CH3
isolated
entry FG
X
yields (%) product b yields (%)
a
a
a
a
1
2
3
4
5
3-F Br
4-F Br
20a
21a
22a
20a
21a
-
-
20b
21b
22b
20b
21b
-
-
2-F
3-F
4-F
I
I
I
33
47
45
24
33
45
a The reaction led either exclusively to the reduction products or to the
mixture of the reduction, dimers and cross-coupled products (<10% GC).
or an unsymmetrical diarylnickel(III) structure (steps 4 and 9,
Scheme 2) through a further oxidative addition. The final
reductive elimination thus produces three possible products, Ar-
Ar (step 15, Scheme 2), Pyr-Pyr (step 12, Scheme 2), and the
expected cross-coupled product (step 5, Scheme 2). Since we
faced a rather statistical product distribution, i.e., a 50% yield
at most in the unsymmetrical biaryl, we could hardly discrimi-
nate the many routes. Actually, several of the reactions reported
gave more than 50% of Ar-Pyr. This can only be explained
through a preferential route among the many possible pathways,
which remains to be ascertained. Our idea is that the first
oxidative addition step from Ni(0) preferably involves the
benzene-type halide (step 2, Scheme 2), while the second
oxdative addition from ArNi(I) would mostly involve the
heteroaryl halide (step 4, Scheme 2).
TABLE 4. Cross-Coupling Reaction between
3-Chloro-6-methoxypyridazine and Heteroaryl Halides
This understanding of the reaction mechanism allowed us to
find a method for improving some couplings. We have
mentioned above that by using a twofold excess of 3-bromoben-
zonitrile vs 3-chloro-6-methoxypyridazine we simply increased
the yield from 27% to 99%.
We monitored by GC analysis the disappearance of substrates
and the formation of products in this cross-coupling reaction
(Figure 2) by varying the reagent ratio. It is important to notice
that reduction products, which were formed more or less
importantly during the electrolysis, have not been reported in
these two figures, as they were not quantified by GC and no
dimer was observed. A typical profile of this coupling reaction
shows that with an equimolar amount of reagents, the substrate
consumption and the cross-product formation first go slowly,
then accelerate after 45 min to reach a maximum after 2 h when
the pyridazine is consumed (Figure 2a), and the cross-coupled
product was isolated in a moderate 27% yield. In similar
conditions, 4-bromobenzonitrile yields 58% of the unsym-
metrical biaryl 6a (entry 6, Table 1). Interestingly, by doubling
the amount of 3-bromobenzonitrile compare to 3-chloro-6-
methoxypyridazine, the profile of the rate of is modified (Figure
2b). Indeed, the cross-coupling proceeds faster and the rate
reaches a maximum as soon as the electrolysis starts leading
efficiently to the cross-coupled product 5a (98% yield). The
excess of 3-bromobenzonitrile has totally been consumed within
2 h leading mainly to the reduction product, which is easy to
remove with a flash-chromatography column. Interestingly, no
dimer of bromobenzonitrile was observed. Conversely, when
conducted with 2 equiv of 3-chloro-6-methoxypyridazine com-
pare to 3-bromobenzonitrile, the efficiency of the cross-coupling
reaction decreased as only 14% of the cross-coupled product
was isolated. These observations clearly indicate that the first
oxidative addition (steps 2 and 7, Scheme 2) is likely to occur
faster with ArX than with PyrX promoting an efficient cross-
a The reaction led exclusively to the reduction products.
coupling reaction occurred with the chloride derivative. Py-
ridazines 24a and 25a were obtained respectively in 83% from
3-bromothiophene and 41% from 2-bromoquinoline (entries 2
and 3, Table 4).
The cross-coupling reaction can be rationalized on the basis
of both the previous investigations by us18 and Budnikova19 as
well as the results detailed in this paper. Scheme 2 summarizes
all the possible reactions within such a reaction mixture
involving the two aryl halides as well as the nickel species.
Various intermediates can be formed and reacted either chemi-
cally or electrochemically.
The active Ni(0) catalyst reductively formed at the cathode
from Ni(II) can react with either the aryl halide or the heteroaryl
halide (steps 2 and 7, Scheme 2). These arylnickel(II) intermedi-
ates can be subjected to a further one-electron reduction into
the reactive arylnickel(I) (steps 3 and 8, Scheme 2). At this key
stage, we reach a two way crossing for each type of arylnickel-
(I) leading to either a symmetrical (steps 14 and 11, Scheme 2)
(18) Ne´de´lec, J.-Y.; Pe´richon, J.; Troupel, M. Top. Curr. Chem. 1997,
185, 141-173.
(19) Budnikova, Yu. G; Kargin, Yu. M.; Sinyashin, O. G. Russ. J. Gen.
Chem. 2000, 70, 116-120.
5634 J. Org. Chem., Vol. 72, No. 15, 2007

Preparation of Aryl- and Heteroarylpyridazines
FIGURE 2. Cross-coupling reaction between 3-bromobenzonitrile and 3-chloro-6-methoxypyridazine.
Typical Workup and Purification. The reaction mixture was
coupling reaction when phenyl halide is added in excess. This
case is particularly favored with meta-EWG-substituted phenyl
halides and less markedly so with the corresponding para-
substituted compound (68% yield with 4-bromobenzonitrile,
entry 6, Table 1). In summary, the mechanism is likely to
proceed through the route depicted in bold in Scheme 2 (steps
1, 2, 3, 4, and 5) leading to the cross-coupled product as the
main product.
poured into a round-bottomed flask and solvents were removed with
a high-pressure pump until dryness. A saturated EDTA solution
(100 mL) was added to the crude oil, and the solution was extracted
with CH2Cl2 containing 2-5% of methanol (4 × 100 mL). The
combined organic layers were dried over Na2SO4, filtered, and
evaporated under vacuum. The crude product was purified by flash
chromatography on silica (200-700 µM), eluted with a gradient
mixture of solvents (pentane/CH2Cl2 40/60 to 100% CH2Cl2, then
CH2Cl2-MeOH until 95/5 for some polar cross-coupling com-
pounds).
Conclusion
Preparation of 3-(6-Methoxypyridazin-3-yl)benzonitrile (5a).
To an undivided electrochemical cell, fitted by an iron rod as the
anode and surrounded by a nickel foam as the cathode, were added
DMF (50 mL), tetrabutylammonium bromide (0.5 mmol, 400 mg),
and 1,2-dibromoethane (2.5 mmol, 215 µL). The mixture was
electrolyzed under argon at a constant current intensity of 0.2 A at
room temperature for 15 min. Then the current was stopped, and
NiBr2bpy complex (0.5 mmol, 187 mg), 3-chloro-6-methoxy-
pyridazine (723 mg, 5 mmol), and 3-bromobenzonitrile (910 mg,
5 mmol) were sequentially added. The solution was electrolyzed
at 0.2 A at room temperature until one of the starting materials
was totally consumed (3 h). The reaction mixture was poured into
a round-bottomed flask and solvents were removed with a high-
pressure pump until dryness. A saturated EDTA solution (100 mL)
was added to the crude oil, and the solution was extracted with
CH2Cl2 containing 2% of methanol (4 × 100 mL). The combined
organic layers were dried over Na2SO4, filtered, and evaporated
under vacuum. The crude product was purified by flash chroma-
tography on silica (200-700 µM) and eluted with a gradient mixture
of solvents (pentane/CH2Cl2 30/70 to 100% CH2Cl2, then CH2Cl2-
MeOH 95/5) to give a white powder (290 mg, 27%). Mp 134-
136 °C. ATR-FTIR (neat, cm-1) 2233, 1595, 1554, 1468, 1418,
We have demonstrated that substituted aryl- and heteroaryl-
pyridazines can be easily prepared in a one-step electrochemical
procedure with moderate to good yields, starting from the
commercially available 3-chloro-6-methoxypyridazine and 3-chlo-
ro-6-methylpyridazine. This methodology can be applied to a
wide range of functional groups on the aryl halide and most of
the prepared compounds are new. Many reactions can give the
cross-coupling products even when an equimolar reagent ratio
is used. Though we did not try to fully optimize each coupling,
we could improve a typical reaction by using a twofold excess
of the phenyl halide, relative to the pyridazine. A reverse ratio
disfavors the cross-coupling reaction. These results have been
taken as being in keeping with the reaction sequence shown in
bold in Scheme 2. We should also notice that we did not vary
the structure of the pyridazines much. It can, however, be
mentioned that the methoxy derivative seems to be more suited
for the cross-coupling reaction, notably within the EWG series
of the phenyl halide.
1
1331, 1305, 1013, 853, 806, 686. H NMR (300 MHz) δ 8.30 (s,
Experimental Section
1H), 8.27 (d, J ) 8.0 Hz, 1H), 7.80 (d, J ) 9.2 Hz, 1H), 7.73 (d,
J ) 7.7 Hz, 1H), 7.61 (t, J ) 7.8 Hz, 1H), 7.11 (d, J ) 9.2 Hz,
1H), 4.201 (s, 3H). 13C NMR (75 MHz) δ 164.7, 164.5, 153.1,
137.4, 132.7, 130.6, 130.1, 129.9, 126.9, 118.5, 118.1, 113.2, 55.1.
MS, m/z (rel intensity) 212 (11), 211 (M+, 100), 210 (65), 183
(17), 182 (66), 155 (12), 140 (62), 129 (19), 113 (19). HRMS m/z
(ES+) calcd for C12H9N3O (M + H)+ 212.0824, found 212.0816.
By working in the same conditions with 2 equiv of 3-bromo-
benzonitrile (1.82 g, 10 mmol) and 1 equiv of 3-chloro-6-
methoxypyridazine (723 mg, 5 mmol), 5a was obtained in 99%
yield (1.04 g) in 2 h and 15 min.
Preparation of 3-(6-Methylpyridazin-3-yl)benzonitrile (5b).
To an undivided electrochemical cell, fitted by an iron rod as the
anode and surrounded by a nickel foam as the cathode, were added
DMF (50 mL), tetrabutylammonium bromide (0.5 mmol, 400 mg),
and 1,2-dibromoethane (2.5 mmol, 215 µL). The mixture was
Typical Procedure for the Cross-Coupling Reactions. To an
undivided electrochemical cell, fitted by an iron rod as the anode
and surrounded by a nickel foam as the cathode, were added DMF
(50 mL), tetrabutylammonium bromide (0.5 mmol, 400 mg), and
1,2-dibromoethane (2.5 mmol, 215 µL). The mixture was electro-
lyzed under argon at a constant current intensity of 0.2 A at room
temperature for 15 min. Then the current was stopped, and NiBr2-
bpy complex20 (0.5 mmol, 187 mg), 3-chloro-6-methoxypyridazine
or 3-chloro-6-methylpyridazine (5 mmol), and aromatic halides (5
mmol) were sequentially added. The solution was electrolyzed at
0.2 A at room temperature until one of the starting materials was
totally consumed (3-4 h).
(20) Troupel, M.; Rollin, Y.; Sock, O.; Meyer, G.; Pe´richon, J. New J.
Chem. 1986, 10, 593-599.
J. Org. Chem, Vol. 72, No. 15, 2007 5635

Sengmany et al.
electrolyzed under argon at a constant current intensity of 0.2 A at
room temperature for 15 min. Then the current was stopped, and
NiBr2bpy complex (0.5 mmol, 187 mg), 3-chloro-6-methylpy-
ridazine (643 mg, 5 mmol), and 3-bromobenzonitrile (910 mg, 5
mmol) were sequentially added. The solution was electrolyzed at
0.2 A at room temperature until one of the starting materials was
totally consumed (3 h and 30 min). The reaction mixture was poured
into a round-bottomed flask and solvents were removed with a high-
pressure pump until dryness. A saturated EDTA solution (100 mL)
was added to the crude oil, and the solution was extracted with
CH2Cl2 containing 2% of methanol (4 × 100 mL). The combined
organic layers were dried over Na2SO4, filtered, and evaporated
under vacuum. The crude product was purified by flash chroma-
tography on silica (200-700 µM), eluted with a gradient mixture
of solvents (pentane/CH2Cl2 20/80 to 100% CH2Cl2, then CH2Cl2-
MeOH 98/2) to give a yellow powder (130 mg, 12%). Mp 167-
169 °C. ATR-FTIR (neat, cm-1) 2226, 1596, 1554, 1461, 1429,
J ) 7.7 Hz, 1H), 7.63 (t, J ) 7.8 Hz, 1H), 7.47 (d, J ) 8.7 Hz,
1H), 2.79 (s, 3H). 13C NMR (100 MHz) δ 159.5, 155.2, 137.6,
133.0, 131.0, 130.4, 129.9, 127.7, 123.9, 118.4, 113.3, 22.0. MS,
m/z (rel intensity) 196 (16), 195 (M+, 100), 167 (33), 166 (57),
140 (21), 127 (75). HRMS m/z (ES+) calcd for C12H9N3 (M +
H)+ 196.0875, found 196.0870.
By working in the same conditions with 2 equiv of 3-bromoben-
zonitrile (1.82 g, 10 mmol) and 1 equiv of 3-chloro-6-methylpy-
ridazine (643 mg, 5 mmol), 5b was obtained in 31% yield (300
mg) in 2 h and 30 min.
Supporting Information Available: Experimental procedures
and characterization data for the preparation of the cross-coupled
1
products 1-25; scanned images of H and 13C NMR spectra for
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
1
1400, 1305, 1001, 846, 801, 681. H NMR (400 MHz) δ 8.59 (s,
1H), 8.33 (d, J ) 8.1 Hz, 1H), 7.80 (d, J ) 8.7 Hz, 1H), 7.75 (d,
JO070429+
5636 J. Org. Chem., Vol. 72, No. 15, 2007