Electrochemical cross-coupling between functionalized aryl halides and 2-chloropyrimidine or 2-chloropyrazine catalyzed by nickel 2,2'-bipyridine complex

Article abstract of DOI:10.1016/S0040-4039(99)02037-7

2-Arylpyrimidines and 2-arylpyrazines have been obtained in good to high yields from 2-chloropyrimidine and 2-chloropyrazine and various functionalized aryl halides by electroreduction using an iron rod as the anode and a catalytic amount of nickel-bipyridine complex in a mixture of DMF and pyridine as solvent.

Full text of DOI:10.1016/S0040-4039(99)02037-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 201–203
Electrochemical cross-coupling between functionalized aryl
halides and 2-chloropyrimidine or 2-chloropyrazine catalyzed by
nickel 2,20-bipyridine complex
Corinne Gosmini,∗ Jean Yves Nédélec and Jacques Périchon
Laboratoire C.N.R.S. d’Electrochimie, Catalyse et Synthèse Organique 2, Rue Henri Dunant 94320 Thiais, France
Received 7 October 1999; accepted 27 October 1999
Abstract
2-Arylpyrimidines and 2-arylpyrazines have been obtained in good to high yields from 2-chloropyrimidine and
2-chloropyrazine and various functionalized aryl halides by electroreduction using an iron rod as the anode and
a catalytic amount of nickel–bipyridine complex in a mixture of DMF and pyridine as solvent. © 1999 Elsevier
Science Ltd. All rights reserved.
In relation to a research project devoted to the synthesis of agrochemicals, a recent paper1 reported
the preparation of 2-alkyl- and 2-arylpyrimidines by coupling between 1,1,3,3-tetramethoxypropane and
amidine hydrochlorides in a sealed tube at 175°C. Yields of 2-substituted pyrimidines were in the range
of 60 to 80%. However, no highlight on the functional group tolerance could be obtained from that work.
Another recently published route to 2-phenyl- or 2-(chlorophenyl)pyrimidine is based on the pyrolysis at
550°C of mixtures of 1-substituted pyrazoles and chloroform.2 Such a route gives poor yields and is far
from being general either. These two methods involve the formation of the heterocyclic ring and require
rather high reaction temperatures. So far, no direct and simple method of access to 2-arylpyrimidines
or -pyrazines from 2-halopyrimidine or 2-halopyrazine and variously substituted aryl halides has been
reported.
We have recently described the arylation of 2-halopyridine and 2-halopyrimidine by electrochemical
processes based on the combined use of a sacrificial anode and a transition metal catalysis.3 They involve
either the electrochemical preparation of an aryl zinc compound followed by its nickel-catalyzed coupling
with 2-chloropyridine or 2-chloropyrimidine, or the direct electroreduction of a mixture of an aryl halide
and 2-halopyridine in DMF in the presence of a catalytic amount of NiBr2Bpy (Eq. (1)).
∗
Corresponding author. E-mail: gosmini@glvt-cnrs.fr (C. Gosmini)
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02037-7
tetl 15965

202
(1)
This latter process was found unsuitable for the synthesis of 2-arylpyrimidine or 2-arylpyrazine,
probably because 2-chloropyrimidine or 2-chloropyrazine are so strongly liganded to the nickel catalyst
that it becomes inefficient, and only reduction products from the reagents were obtained.
We have now disclosed that the presence of iron salts at the beginning of the electrolysis could
circumvent this problem. They are formed by oxidation of an iron anode along with the reduction of
1,2-dibromoethane prior to the introduction of the reagents. Then the usual electrolysis in the presence
of the iron anode allows the desired coupling reaction to occur efficiently, as shown in Table 1 for the
arylation of 2-chloropyrimidine according to Eq. (2).
(2)
The coupling procedure is thus as follows: In an undivided cell flushed with argon, equipped with
an iron rod as the anode and a nickel foam as the cathode, were introduced DMF (40 ml) and pyridine
(10 ml), 1,2-dibromoethane (2 mmol) and NBu4BF4 (1 mmol) as the supporting electrolyte. A constant
current intensity of 0.2 A was applied at room temperature until a charge of 2 F per mol of the halides
had passed. Then the solution was heated at 60°C and we introduced NiBr2Bpy (1 mmol) as the catalyst
precursor, the aryl halide (3.75 mmol) and 2-chloropyrimidine (or 2-chloropyrazine) (3.75 mmol). A
current intensity of 0.2 A was applied until a charge of 2 F per mol of halide had passed. We then again
introduced aryl halide (3.75 mmol) and 2-chloropyrimidine (or 2-chloropyrazine) (3.75 mmol) and the
electrolysis was carried out with the same current intensity until complete consumption of the starting
reagents.
According to our previous studies,3 we assume that FG-C6H4NiX is the first formed intermediate,
being further reduced to FG-C6H4Ni to react preferably with 2-chloropyrimidine or 2-chloropyrazine.
We also know that 2-chloropyrimidine and 2-chloropyrazine are more reactive than 2-chloropyridine.4
This implies that, for the coupling reaction to be efficient, we should have the right halogen on the aryl
halide according to the nature of the substituent, i.e. bromine with an electron withdrawing group, and
iodine with an electron-donating group.
Under the same reaction conditions, 2-chloropyrazine is directly coupled in good yield with aryl
bromide substituted by an electron-withdrawing group (Eq. (3)).
(3)
This process has been successfully applied with the halide on pyrimidine at another position; the
coupling of 4-chloropyrimidine also bearing an electron-donating group is also possible (Eq. (4)).

203
Table 1
Electrochemical cross-coupling between 2-chloropyrimidine and substituted aryl halides
(4)
In conclusion, we have shown that it is possible to prepare various 2-arylpyrimidine, 2-arylpyrazine
and 4-arylpyrimidine using a very simple electrochemical process.
References
1. Wang, T.; Cloudsdale, I. S. Synth. Commun. 1997, 27, 2521–2526.
2. Bhatti, I. A.; Busby, R. E.; bin Mohamed, M.; Parrick, J.; Granville Shaw, C. J. J. Chem. Soc., Perkin Trans. 1 1997,
3581–3585.
3. Gosmini, C.; Lasry, S.; Nédélec, J. Y.; Périchon, J. Tetrahedron 1998, 54, 1289–1298.
4. Boulton, A. J.; McKillop, A. In Comprehensive Heterocyclic Chemistry, Vol. 2, Part 2A; Boulton, A. J.; McKillop, A., Eds.;
Pergamon Press: Oxford, 1984; chap. 2.02, p. 59.