Functionalized 2,5-dipyridinylpyrroles by electrochemical reduction of 3,6-dipyridinylpyridazine precursors

Article abstract of DOI:10.1002/ejoc.200701115

The ring contraction of pyridinylpyridazine derivatives into the corresponding pyrroles by electrochemical reduction was studied, and the influence of the substituents of the pyridazine precursors on the process is discussed. Cyclic voltammetry studies underlines the electron-withdrawing or -donating effect of the substituent on the pyridazine ring, which determines the reaction pathway of their preparative electrolysis. The ring-contraction process, with extrusion of nitrogen, proceeds by two subsequent two-electron, two-proton processes via a 1,2-dihydropyridazine intermediate. The latter can either rearrange into an isolable 1,4-dihydropyridazine or undergo formation of pyrroles by disproportionation or by a second electrochemical reduction involving two-electrons and two protons. X-ray structure, fluorescence spectra, and conformational analysis of pyridinylpyrrole sequences supported this study. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701115

FULL PAPER
DOI: 10.1002/ejoc.200701115
Functionalized 2,5-Dipyridinylpyrroles by Electrochemical Reduction of
3,6-Dipyridinylpyridazine Precursors
Hicham Bakkali,[a,b] Cécile Marie,[a,b] Akarim Ly,[c] Christine Thobie-Gautier,[a,b]
Jérôme Graton,[a,b] Muriel Pipelier,[a,b] Stéphane Sengmany,[d] Eric Léonel,[d]
Jean-Yves Nédélec,[d] Michel Evain,[e] and Didier Dubreuil*[a,b]
Keywords: Nitrogen heterocycles / Ring contraction / Electrochemistry / Reduction
The ring contraction of pyridinylpyridazine derivatives into
the corresponding pyrroles by electrochemical reduction was
studied, and the influence of the substituents of the pyrid-
azine precursors on the process is discussed. Cyclic voltam-
metry studies underlines the electron-withdrawing or -donat-
ing effect of the substituent on the pyridazine ring, which
determines the reaction pathway of their preparative elec-
trolysis. The ring-contraction process, with extrusion of nitro-
gen, proceeds by two subsequent two-electron, two-proton
processes via a 1,2-dihydropyridazine intermediate. The lat-
ter can either rearrange into an isolable 1,4-dihydropyrid-
azine or undergo formation of pyrroles by disproportionation
or by a second electrochemical reduction involving two-elec-
trons and two protons. X-ray structure, fluorescence spectra,
and conformational analysis of pyridinylpyrrole sequences
supported this study.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
medium proceeds by a four-electron reduction process to
give the corresponding 2,5-bis(methoxycarbonyl)pyrroles 5
according to the mechanism shown in Scheme 1.[8,9]
Introduction
Pyrroles are very important heterocycles used in materi-
als science,[1] especially when incorporated into conjugated
chains, because of their conducting and optical proper-
ties.[2,3] Pyrroles are also involved as structural moieties in
many naturally occurring biologically active compounds[4]
such as marine pyrrole-based alkaloids[5] and pyrrole–imid-
azole alkaloids,[6] and they have gained importance in the
field of medicinal chemistry.[7]
Among the many strategies available to form pyrrole de-
rivatives, chemical ring contraction of larger rings is one
important tool that has long been described in the litera-
ture.[7] This methodology affords pyrrole derivatives with
varied substituents, which are otherwise difficult to synthe-
size. Recently, we showed that electrochemical transforma-
tions of 3,6-bis(methoxycarbonyl)pyridazines 1 in an acidic
Scheme 1. Mechanism for the electrochemical reduction of bis-
(methoxycarbonyl)pyridazines.
The electrochemical reduction of 4,5-substituted 3,6-bis-
(methoxycarbonyl)pyridazines 1 affords a mixture of 1,4-
dihydropyridazines 3 and pyrroles 5, according to the na-
ture of the C4 and C5 substituents (RЈ and RЈЈ). The prod-
uct distribution is governed by the chemical behavior of the
1,2-dihydropyridazine intermediate 2 formed by the first
[a] Université de Nantes, CEISAM, Chimie Et Interdisciplinarité,
Synthèse, Analyse, Modélisation, UFR des Sciences et des
Techniques,
2 rue de la Houssinière, B. P. 92208, 44322 Nantes Cedex 3,
France
[b] CNRS, UMR CNRS 6230
2 rue de la Houssinière, B. P. 92208, 44322 Nantes Cedex 3, two-electron reduction of the pyridazine precursor 1. Dihy-
France
dropyridazine 2 can either be oxidized back into the start-
[c] Département de Génie Chimique, Université de Conakry,
ing material, as clearly shown by cyclic voltammetry,[9] or
Guinea
[d] Electrochimie et Synthèse Organique, Institut de Chimie et des
Matériaux Paris-Est UMR 7182 – CNRS, Université Paris 12,
2 rue Henri-Dunant, 94320 Thiais, France
rearrange into the 1,4-dihydropyridazine 3. Both dihy-
dropyridazine intermediates 2 and 3 can be further reduced
by another two-electron process to give the corresponding
pyrrole 5 by two different chemical pathways a and b via
the corresponding iminium intermediates 4a and 4b, respec-
tively (Scheme 1). Moreover, 1,2-dihydropyridazine 2 can
[e] Université de Nantes, Nantes Atlantique Universités, CNRS,
Faculté des Sciences et des Techniques, Institut des Matériaux
Jean Rouxel, UMR CNRS 6502,
2 rue de la Houssinière, B. P. 92208, 44322 Nantes Cedex 3,
France
2156
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Functionalized 2,5-Dipyridinylpyrroles by Electrochemical Reduction
also disproportionate into the starting pyridazine and the Electrochemical Behavior of the Substituted Pyridazines
expected pyrrole. If the isomerisation of 2 into 3 is fast, the
In our previous study,[9] we showed that the electrochemi-
amount of pyrrole can be considerably decreased, as the
cal reduction of 3,6-bis(methoxycarbonyl)pyridazine pro-
ceeds in three successive bielectronic steps [E1/2 = –0.69,
–0.86, –1.07 V/SCE (saturated calomel electrode)] with a re-
electroreduction of 1,4-dihydro derivative 3 is not the fa-
vored way to form pyrroles.
It comes out that the electrochemical process is very sen-
sitive to the nature of the functionalities on the substrate.
versibility of the first step in cyclic voltammetry in acetate
buffer/ethanol (1:1) at a scan rate of 0.2 Vs–1. Moreover,
Indeed, 3,6-bis(methoxycarbonyl)pyridazine bearing
a
when the potential was scanned down to the level of the
second wave (E1/2 = –0.86 V/SCE), a new reversible step
was observed at a more anodic potential at around +0.1 V/
SCE.
Also, in our previous experiments carried out on 3,6-di-
pyridinylpyridazines 9 and 14,[9] we found that the first po-
larographic reduction wave (E1/2 = –0.75 V/SCE) corre-
sponds to an irreversible four-electron transfer, whereas the
next two waves are not well defined and are masked by
adsorption peaks.
We have now complemented this previous study by the
electrochemical investigation of the substituted dipyridinyl-
pyridazines 9–17 in acetate buffer/ethanol medium to estab-
lish the favorable general conditions for their controlled po-
tential electrolysis. In each case, the polarography or cyclic
voltammetry experiments[22] displayed three defined
irreversible steps.
phenyl group at C4 allowed the formation of the corre-
sponding pyrrole in 70% high yield, whereas the 3,4,5,6-
tetrakis(methoxycarbonyl) analogue gives rise to the corre-
sponding 1,4-dihydro derivative 3 as the sole product.
We investigated a complementary study of a C4 substitu-
ent effect on the electrochemical reduction of 3,6-dipyridin-
ylpyridazines providing functionalized 3,6-dipyridinylpyr-
role analogues. The study was carried out in comparison
with the conventional chemical ring-contraction procedure
extensively used by Boger (Zn/AcOH in acidic me-
dium).[10,11] The interest of the synthesis of such a substi-
tuted dipyridinylpyrrole sequence is highlighted by a variety
of applications of biological interest,[12,13] or as potent an-
ionic complex agents with organometals,[14] or as cationic
ligands when linked to amidinium or guanidinium salts to
allow interaction with DNA or RNA sequences.[15,16]
Figure 1 shows the cyclic voltammograms of pyridazine
9, used as a reference model, at a glassy carbon electrode in
acetate buffer/ethanol at two different scan rates (0.2 Vs–1
Figure 1A and 2ϫ10–3 Vs–1 Figure 1B). Voltammetry per-
formed at a mercury electrode or a solid glassy carbon elec-
trode gave the same profile despite an anodic potential shift
(0.04 V) with the mercury electrode. Therefore, the glassy
carbon electrode was selected for the voltammetry studies.
Results and Discussion
Preparation of the Dipyridinylpyridazine Precursors
The preparation of 4-substituted 3,6-dipyridin-2-ylpyrid-
azines and -4-ylpyridazines 9–14 and those of 3,6-bis(6-
methylpyridin-2-yl- and -4-yl)pyridazines 15–17 was carried
out following a well-described procedure from 2- and 4-cya-
nopyridine precursors (Scheme 2).[15,17,18] Diels–Alder reac-
tions from 3,6-dipyridinyltetrazine intermediates 6, 7, or 8
in the presence of various dienophiles led to the targeted
pyridazines 9–17 in good yields after extrusion of molecular
nitrogen (Table 1).
Figure 1. Cyclic voltammograms at a glassy carbon electrode in
acetate buffer/ethanol (1:1) (---) and in the presence of 9 (___) (C =
10–3 molL–1) at a scan rate of 0.2 Vs–1 (A) and 2ϫ10–3 Vs–1 (B).
Scheme 2. Pyridazine synthetic pathway.
The cyclic voltammogram of 3,6-dipyridin-2-ylpyridaz-
ine 9 recorded at 0.2 Vs–1 displays two well-defined irrevers-
ible cathodic peaks (I and II) along with a poorly defined
wave at a more cathodic potential (III). It is important to
notice that no reversibility is observed at any reduction step,
contrary to the reversibility reported in the case of 3,6-
bis(methoxycarbonyl)pyridazines.[9] On the basis of our
mechanistic hypothesis, peak I, at EpI = –0.88 V/SCE, cor-
responds to the first two-electron reduction of pyridazine,
Table 1. Yield of pyridazines obtained by Diels–Alder reaction.
Pyridazine
R
R1
Yield [%] Ref.
[19,20]
9
pyridin-2-yl
pyridin-2-yl
pyridin-2-yl
pyridin-2-yl
pyridin-2-yl
pyridin-4-yl
6-methylpyridin-2-yl
6-methylpyridin-2-yl (CH2)3CH3 84
6-methylpyridin-2-yl (CO2)C2H5 97
H
92
[20]
10
11
12
13
14
15
16
17
(CH2)3CH3 91
[20]
(CH2)2OH
OC2H5
(CO2)C2H5
H
71
40
82
93
98
[21]
H
which leads to
a 1,2-dihydropyridazine intermediate,
whereas peak II (EpII = –1.06 V/SCE) represents the second
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D. Dubreuil et al.
FULL PAPER
two-electron reduction of the latter into the pyrrole ring. electron-withdrawing group (13). Moreover, a large varia-
Furthermore, the last wave III can be assigned to the re- tion in the current intensity of peaks I and II was observed
duction of the pyrrole derivative. That was confirmed by depending on the nature of R1. Cyclic voltammograms of
the cyclic voltammogram of the pure pyrrole 18, which pyridazines 10 and 13 bearing an electron-donating (Bu)
presents a single cathodic peak at –1.35 V/SCE. Conse- and electron-withdrawing substituent (CO2Et), respectively,
quently, the first two peaks I and II, which illustrate the illustrate the actual trends (Figure 2).
four-electron and four-proton transfers, are assignable to
the complete transformation of the pyridazine ring into
pyrrole following the extrusion of
a nitrogen atom
(Scheme 3, Path a). Would the process follow Path a, how-
ever, we should have the two peaks I and II of the same
current intensity corresponding to two two-electron pro-
cesses. This is not observed, and the ratio of IpI/IpII is 2.5,
which thus indicates more than two and less than four as
the electrons transferred at wave I. At a lower scan rate of
2 mVs–1, the peak ratio is even greater, and peak III is also
more intense. These observations can be explained by a
poor stability in acidic solution of the first-formed 3,6-dipy-
ridin-2-yl-1,2-dihydropyridazine intermediate and its rather
rapid disproportionation into the starting pyridazine and
the pyrrole (Scheme 3, Path b), which thus accounts for the
increase in the current intensities of peaks I and III, respec-
tively.[8,9]
Figure 2. Cyclic voltammograms at a glassy carbon electrode in
acetate buffer/ethanol (1:1) of compounds 9 (---), 10 (–––), and 13
(–––) (C = 10–3 molL–1) at a scan rate of 0.2 Vs–1.
The effect of an electron-donating group (R1 = Bu, 10;
R1 = C2H4OH, 11) results in a significant increase in the
current of peak I relative to the current of peak II (IpI/
IpII = 10). This observation indicates that, after the first
reduction step, the 1,2-dihydropyridazine intermediates
evolve rapidly in acidic medium to give the expected pyr-
roles 19 and 20, respectively, either after another two-elec-
tron reduction (Scheme 3, Path a) or by disproportionation
(Scheme 3, Path b). However, the decrease in the IpI/IpII
ratio to 3 in the presence of an OEt donating group high-
lighted the sensibility of the equilibrium of the processes
and anticipates different behaviors under preparative elec-
trolyses.
Scheme 3. General transformation pathway of pyridazines into pyr-
roles.
The effects of the substitution (R1) of the pyridazine
In the case of an electron-withdrawing substituent (R1 =
moieties on their electrochemical behavior were then evalu- CO2Et, 13), current intensities of peaks I and II are nearly
ated in comparison with pyridinylpyridazine 9 and 6-meth- equal (IpI/IpII = 1.3). This result is explained by stabiliza-
ylpyridinylpyridazine 15, used as reference compounds (R1 tion of the 1,2-dihydropyridazine intermediate by the sub-
= H). Table 2 reports the data for the first two cathodic stituent. Consequently, the reduction of the latter to the
peaks I and II measured for the two series 10–13 and 16–17 corresponding pyrrole 22 by consuming two more electrons
(the ratio IpI/IpII was determined at a scan rate of 0.2 Vs–1). and two more protons (Scheme 3, Path a) is in competition
We noticed that the reduction potential values are only with the formation of the 1,4-dihydropyridazine intermedi-
slightly influenced by the nature of R1. As expected, and in ate.
comparison to the cyclic voltammograms of pyridazine 9,
Differences in the potential observed between the first
a small negative potential shift was induced by an electron- two reduction peaks (∆Ep) also led to the same conclusion.
donating group (10–12) and vice versa in the presence of an Indeed, the values of ∆Ep are smaller in the case of elec-
Table 2. Cyclic voltammetry data of substituted pyridazines at a glassy carbon electrode, Ep (V/SCE) and v = 0.2 Vs–1.
Pyridazine
R
R1
EpI
EpII
∆Ep[a]
IpI/IpII
9
pyridin-2-yl
pyridin-2-yl
pyridin-2-yl
pyridin-2-yl
pyridin-2-yl
pyridin-4-yl
6-methylpyridin-2-yl
6-methylpyridin-2-yl
6-methylpyridin-2-yl
H
–0.88
–0.89
–0.92
–0.99
–0.71
–0.79
–0.83
–0.85
–0.71
–1.06
–1.08
–1.11
–1.18
–0.99
–0.97
–1.01
–1.05
–1.01
0.18
0.19
0.19
0.19
0.28
0.18
0.18
0.20
0.30
2.5
10
10
3
1.3
2
2.5
15
1
10
11
12
13
14
15
16
17
(CH2)3CH3
(CH2)2OH
OC2H5
CO2C2H5
H
H
(CH2)3CH3
CO2C2H5
[a] ∆Ep = EpII – EpI.
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Functionalized 2,5-Dipyridinylpyrroles by Electrochemical Reduction
tron-donating substituents (∆Ep ≈ 0.19 V for 10–12) than odic compartment and the electrolyses stopped when the
for electron-withdrawing groups (∆Ep ≈ 0.28 V for 13 and starting substrate was consumed. Then, all preparative elec-
∆Ep ≈ 0.30 V for 16), which confirms a preferred dismu- trolyses were performed within 4–6 h, compared to the18 h
tation occurrence in the presence of electron-donating required under chemical Zn/AcOH conditions.
groups.
Similar results were obtained in the (6-methylpyridinyl)- cal reduction, measured by coulometry, corresponded ap-
pyridazine series 15–17 (∆Ep ≈ 0.18, 0.20, 0.30; IpI/IpII proximately to four electrons per mole of pyridazine, as ex-
The electricity consumption of preparative electrochemi-
=
2.5, 15, 1.0, respectively, for 15, 16, 17), which underlines pected. This was not the case, however, for pyridazines 13
that the methyl substituent on the pyridinyl group does not and 17, which contain an electron-withdrawing substituent
have a significant influence on the electrochemical behavior (R1 = CO2Et), where the amount of consumed electrons
of the pyridazines.
was significantly higher than 4e– (5 to 6e–). This latter result
These observations highlighted the versatility of the elec- suggests that degradation should occur partially in this
trochemical process related to the nature of the substituents series.
present at different positions on the pyridazine precursors,
Thus, yields of isolated 2,5-dipyridin-2- and -4-ylpyrroles
and this was considered complementary to what was al- 18–20 and 23 obtained by electrolysis of pyridazines 9–11
ready established in the literature, which was that electron- and 14, respectively, were all up to 80%, whereas the trans-
donating groups at the 3,6-positions disfavor the ring-con- formation of pyridazine 13 (R1 = CO2Et) into pyrrole 22
traction process. Consequently, the variation in the yield of was only achieved in a modest 53% yield. The loss of yield
2,5-dipyridinylpyrrole formation by preparative electrolyses observed in the formation of pyrrole 21 from 4-ethoxypyri-
of 3,6-dipyridinylpyridazine should be anticipated.
dazine 12 (68%) highlighted the sensitive step of the electro-
chemical reduction process, occurring at the level of 1,2-
and 1,4-dihydro intermediates equilibrium, which seems
sensitive to the stronger donor effect of the ethoxy group.
The introduction of a methyl substituent on the pyridinyl
rings has a surprising influence on the electrochemical syn-
thesis of the corresponding pyrroles and yields 77% of 24,
72% of 25, and 37% of 26, without any trace of 1,4-dihy-
dropyridazine intermediates. By taking into account the
previous voltammetry analysis, this observation should be
ascribed to the solubility of the latter in the experimental
acidic medium.
Preparative Electrolyses of Substituted Pyridazines
In order to optimize the electrochemical formation of
pyrrole derivatives, a series of controlled potential electro-
lyses of pyridazines 9 to 17 was performed at the second
reduction peak potential (EpII). The experiments were car-
ried out in a mixture of acetate buffer (pH = 4.6) and etha-
nol (1:1) at a mercury pool cathode in the two-compart-
ment cell by using a glass frit. The results of electrochemical
reductions are summarized in Table 3 along with, for com-
parison, the yields obtained by the alternative ring-contrac-
tion chemical procedure (Scheme 4). Reactions were moni-
tored by cyclic voltammetry measurement within the cath-
However, these results also confirm the unfavorable ef-
fect of electron-withdrawing groups at C4 of the pyridazine
residues on the electrochemical pathway. Nevertheless, all
the transformations of pyridazines 9 to 17 are advan-
tageously compared to those obtained by the chemical
route, using a Zn/ACOH medium, which afforded the corre-
sponding pyrroles 18–26 in only low yields (15 to 30%).
Next, preparative electrolyses were also performed at the
potential of the first reduction peak (EpI) of the pyrid-
azines. These experiments were carried out to investigate
whether pyridazines could evolve through the sole dismu-
tation process to the corresponding pyrroles (Scheme 3,
Table 3. Coulometric data and yields of substituted pyrroles by
electrochemical or chemical syntheses.
Pyridazine
n
Time
[h] CPE
Pyrrole
Yield
Yield
[Fmol–1
]
[%] CPE[a] [%] Zn/AcOH
9
4.1
4.5
4.5
4.5
5.6
3.8
4.4
4.2
5.2
4.6
6.0
5.3
5.2
6.2
4.0
3.2
4.8
4.9
18
19
20
21
22
23
24
25
26
82
87
92
68
53
85
77
72
37
22
18
15
30
37
30
17
20
22
10
11
12
13
14
15
16
17
Path b). Results with pyridazines 9 (R1 = H), 10 (R1
=
Bu), 12 (R1 = OEt), and 13 (R1 = CO2Et) are presented in
Table 4.
[a] Electrolysis at a controlled potential at the second reduction
peak (EpII).
Table 4. Coulometric data and yields of substituted pyrroles by
electrochemical synthesis. The potential of the first reduction peak
Ep1 was applied.
Pyridazine
F/mol
Time
[h] CPE
Pyrrole
(yield, %)
Dihydropyridazine
(yield, %)
9
4.1
4.0
3.0
2.1
7.0
7.0
6.5
4.1
18 (72)
19 (78)
21 (70)
22 (0)
–
–
10
12
13
27 (12)
28 (75)
Scheme 4.
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In the case of pyridazines 9, 10, and 12, four electrons
Conformational analysis of the 2,5-dipyridin-2-ylpyrrole
per mol of pyridazine were logically consumed to yield the 18 structures was investigated and it was revealed that, on
corresponding pyrroles in over 70% yield. Under these par- the one hand, three nonequivalent minima can be found,
ticular electrochemical conditions, the formation of pyrroles all of which show coplanar rings (φNCCN = 0.0° and 180.0°)
supports our ring-contraction mechanism hypothesis. In- as illustrated in Figure 4. On the other hand, transition
deed, 1,2-dihydropyridazine intermediates formed from un- states TSs present two perpendicular rings (φNCCN = 95.0°).
substituted or electron-donating substituted pyridazines The symmetry of this system leads to a symmetric confor-
(Scheme 3, Path b) are unstable in acidic medium and un- mational profile (Figure 5) on both sides of the global ener-
dergo a disproportionation process to yield the concomi- getic minimum. This latter (named syn–syn) is characterized
tant formation of pyrroles and starting pyridazines, which by the two pyridinyl nitrogen atoms in syn position towards
can be involved in a further reduction process. Conse- the pyrrole nitrogen atom. The two local minima are de-
quently, the reaction time (7 h) was longer than the electrol- scribed by the anti position of one (syn–anti conformer) or
ysis run at the stage of the second reduction wave (5 h). No both (anti–anti conformer) pyridinyl nitrogen atoms. These
formation of 1,4-dihydropyridazine was observed during rotations result in destabilizations of 14.2 and 35.2 kJmol–1,
the transformation of 9 and 10, whereas 4-ethoxy-1,6-dihy- respectively, by comparison to the absolute minimum. The
dropyridazine 27 was identified as an isolable intermediate, two similar rotation barriers, found on passing from the
in 12% yield, from 12 (Figure 3). The latter was particularly syn–syn to the syn–anti conformer (30.6 kJmol–1), and from
1
characterized in the H NMR spectrum by two 1H singlets the syn–anti to the anti–anti conformer (33.9 kJmol–1),
at δ = 6.43 and 4.92 ppm.
show that they are surmountable at room temperature. The
different conformers are therefore considered to be in equi-
librium with each other, and the relative syn–syn and syn–
anti populations are about 99.0 and 1.0%, respectively,
whereas the anti–anti population can safely be predicted to
be present in negligible amounts.
The surprising preferred syn–syn structure is explained
by the two bifurcated NΛH–N interactions, which are weak
Figure 3. Dihydropyridazine derivatives obtained as a byproduct
(27) or sole compound (28) of the electrochemical reduction run at
the potential of the first reduction peak (Ep1) of the corresponding
pyridazine 12 and 13, respectively.
but significant intramolecular hydrogen bonds (dNΛH
=
2.475 Å, 7% shorter than the sum of the van der Waals ra-
dii[23]). Conversely, the syn–anti rotamer is significantly less
stable due to a single hydrogen-bond interaction, despite
In the presence of electron-withdrawing groups (R1
=
CO2Et, 13), only 2.1 electrons, which correspond to the first the fact that it is stronger and slightly more favorable, (dNΛH
potential wave of the pyridazine reduction, were consumed. = 2.381 Å, θNΛH–N = 98.0° against 93.7° in syn–syn), and
The formation of pyrrole 22 was then not detected and 1,4- in addition, to a significant repulsion between two close
dihydro-5-methoxycarbonylpyridazine derivative 28 (Fig- hydrogen atoms (dHΛH = 2.178 Å). In contrast, the anti–
ure 3) was isolated in 75% yield as the sole product of the anti rotamer presents two HΛH repulsions and no NΛH–
reaction. This result shows that the disproportionation pro- N interaction. The propensity of pyrrole derivatives to form
cess is inhibited in the presence of an electron-withdrawing bifurcated hydrogen bonds has previously been under-
substituent on the pyridazine ring, and consequently, the lined.[24] Relative energies between syn and anti conformers
1,2-dihydropyridazine intermediate spontaneously re- of 2-(pyridin-2-yl)pyrrole and 5-(pyridin-2-yl)-2-(trifluo-
arranges into a more stable 1,4-dihydropyridazine deriva- roacetyl)pyrrole at the B3LYP/6-311G(d,p) level are in
tive. The structure of the latter was established by the pres- good agreement with those found in this work, as well as
ence of a 2H singlet for the methylene group at δ = the geometrical parameters of the intramolecular inter-
1
3.65 ppm in H NMR spectroscopy.
actions.
Figure 4. Minima and transition-state conformers of 2,5-dipyridin-2-ylpyrrole 18 found at the MPWB1K/6-31+G(d,p) level.
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Functionalized 2,5-Dipyridinylpyrroles by Electrochemical Reduction
Figure 5. Conformational profile of 2,5-dipyridin-2-ylpyrrole 18 obtained at the LMP2/6-311++G(d,p)//MPWB1K/6-31+G(d,p) level
with relative energies and rotation barriers.
Theoretical prediction on the stable conformation of 2,5- ure 6). The packing is conveniently obtained by a criss-
dipyridin-2-ylpyrroles was confirmed by X-ray analysis of crossed association, in which the molecules are aligned into
pyrrole 18[25] (Figure 6) and compared with dipyridin-4-yl- two close-to-90° directions to yield double-layer-like sub-
pyrrole analogue 23[26] (Figure 7), in the solid state.
structures.
The experimental conformation observed in the crystal-
line state is just slightly distorted towards the absolute mini-
mum owing to the packing constraints, with two slightly
different orientations of the pyridinyl groups towards the
pyrrole ring (φNCCN = –0.1 and 12.0°). The superposition
of the 17 heavy atoms, which gives an associated RMS devi-
ation of 0.118 Å, illustrates the great similarity of these two
structures. The RMS deviation is greatly decreased
(0.044 Å) when the superposition is achieved only on the
two coplanar rings (Figure 8). In contrast to the theoretical
structure, pyridinyl rings show two different bifurcated
NΛH–N interactions (dNΛH = 2.472 Å and dNΛH = 2.574 Å)
owing to their nonequivalent orientations. However, the
shortest contact is in good agreement with those measured
in the optimized syn–syn conformer (dNΛH = 2.475 Å).
Figure 6. ORTEP diagram of dipyridin-2-ylpyrrole 18.
Figure 7. ORTEP diagram of dipyridin-4-ylpyrrole 23.
Figure 8. Superposition of the experimental (gray) and the theoreti-
cal (pale gray) structures of 2,5-dipyridin-2-ylpyrrole. An RMS de-
viation value of 0.044 Å was calculated by taking into account the
two coplanar rings.
In the case of 2,5-dipyridin-4-ylpyrrole 23 (Figure 7), the
packing of the C14H11N3 molecules occurs through H-
bonded water molecules. Each C14H11N3 molecule is linked
to five symmetrically equivalent molecules through three
water molecules, which results in a pattern that extends
throughout the crystal to give a complex three-dimensional
The absorption and the fluorescence properties of the py-
network. In contrast, molecules of 2,5-dipyridin-2-ylpyrrole ridinylpyrrole derivatives were complementarily studied.
18 assemble through van der Waals interactions only (Fig- For all the different pyrroles, the general absorption and
Eur. J. Org. Chem. 2008, 2156–2166
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2161

D. Dubreuil et al.
FULL PAPER
used for column chromatography. Mass spectra were measured
with a quad. Hewlett Packard 5989A. HRMS were measured with
a MS–MS ZABSpec TOF spectrometer from Micromass (Positive
Electrospray, solvent: MeOH) and were performed at the “Centre
Régional de Mesures Physiques de l’Ouest”, Rennes, France. FTIR
spectra were obtained in the 500–4000 cm–1 range with a Bruker
Vector 22 FTIR spectrometer by using NaCl pellets. Fluorescence
spectra were recorded with a SPEX Fluoromax fluorimeter.
fluorescence characteristics were quite similar and no effect
of substituents was noticeable.[27] The fluorescence spectra
of pyrroles 19, 24, 25, and 26 are exemplified in Figure 9.
General Procedure A. Preparation of 2,6-Dipyridinyl-1,2,4,5-tetraz-
ine: A solution of cyanopyridine (1 mmol) and hydrazine hydrate
(4 mmol), used as solvent, was heated at reflux for 4–5 h (if dissol-
ution of cyanopyridine was difficult few milliliters of EtOH were
added to the mixture). After cooling to 0 °C, the expected dihy-
drotetrazine precipitated and was then filtered and washed with
diethyl ether. The yield is quite quantitative.
After dissolution of the dihydrotetrazine in AcOH (20 mL) and
H2O (14 mL), the mixture was cooled to 0 °C. A solution of
NaNO2 (10 mmol) in H2O (2 mL) was then added drop by drop.
The reaction mixture immediately turned pink and stirring was
pursued for 1 h at 0 °C after the end of the addition. The mixture
was then neutralized with an ammonia solution (33% aqueous
solution). The precipitate obtained was then filtered, washed with
cold water, and dried under high vacuum.
Figure 9. Fluorescence spectra of pyrroles 19, 24, 25, and 26.
General Procedure B. [4+2] Cycloaddition Access to Dipyridinylpyr-
idazine: A solution of tetrazine (1 mmol) and dienophile (2 mmol)
in the appropriate solvent (toluene, DMF, or dioxane) was heated
for several days (the disappearance of the intense purple color of
Conclusions
Results obtained in this study emphasize the potential
for substituted pyrroles to be formed by an electroreduction the tetrazine indicates the progress of the reaction). After evapora-
tion of the solvent under reduced pressure, the crude product was
purified by column chromatography on Al2O3 or by precipitation.
pathway, which was performed from 4-substituted 3,6-dipy-
ridinylpyridazines. The electrochemical ring-contraction
process involves four electrons and four protons, in an
acidic medium, and is efficient in the presence of pyridinyl
groups at the C3 and C6 positions of the pyridazine moiety.
Inductive electron-donating groups at the C4 position seem
to facilitate the ring-contraction process However, electron-
withdrawing groups and mesomeric electron-donating ef-
fects affected significantly the formation of pyrroles.
General Procedure C. Chemical Ring Contraction: To a solution of
pyridazine (1 mmol.) in glacial acetic acid (11 mL) heated at reflux
was added activated zinc dust (20 mmol.). The reaction was moni-
tored by TLC. After completion, the mixture was cooled, filtered
trough a pad of Celite, and concentrated under reduced pressure.
The crude residue was purified by flash chromatography on silica
gel.
General Procedure D. Electrochemical Ring Contraction
An application of these small pyridinylpyrrolo deriva-
tives in the interaction with the genomic human
tRNAARNt3Lys, a natural primer of all immunodeficient
Cyclic Voltammetry: Experiments were performed by using a po-
tentiostat–galvanostat EGG PARC Model 273 controlled by the
Echem software. A conventional three-electrode system was used
with a glassy carbon working electrode, a saturated calomel refer-
ence electrode (SCE), and a platinum wire counter electrode.
viruses, is in course.[29,30] The binding of 2,5-pyridinylpyr-
Lys
role analogues 18–26 on tRNAARNt3
has been evalu-
ated by 600 MHz NMR spectroscopic studies.[28–30] Their
selectivity and their ability to be used as inhibitors for re-
verse transcription of HIV-1 viral RNA will be discussed
elsewhere.
Preparative Electrolyses: Experiments were carried out at a mercury
pool electrode (diameter 4.7 cm) at a constant cathodic potential
in the two compartments cell separated by a glass frit. The cathodic
compartment contained acetic buffer (0.1 molL–1, pH = 4.6,
50 mL), ethanol (50 mL), and the pyridazine substrate
(7ϫ10–4 mol). Prior to and during electrolysis, the catholyte was
deaerated with argon and stirred magnetically. The constant poten-
tial (value corresponding to the second reduction peak of the sub-
strates versus the saturated calomel electrode) was imposed by a
potentiostat–galvanostat EGG PARC Model 273. The course of
the reaction was followed by cyclic voltammetry in the cathodic
compartment, and the electrolysis was stopped when the consump-
tion of the starting substrate was completed. After evaporation of
ethanol, the aqueous solution was neutralized with NaHCO3 and
extracted with CH2Cl2. When necessary, the pyrrole derivative was
purified by column chromatography on alumina.
Experimental Section
Solvents were purified and dried by standard methods prior to
use.[31] All reactions were carried out under an atmosphere of ar-
gon. 1H and 13C NMR spectra were recorded with a Bruker AC
300 with TMS as an internal standard for 1H spectra. Chemical
shifts (δ) are given in ppm and coupling constants (J) in Hz with
the following abbreviation for signal multiplicity: s for singlet, br.
s for broad singlet, d for doublet, br. d for broad doublet, t for
triplet. All reactions were monitored by TLC on commercially
available precoated plates (Kieselgel 60 F254), and the products
were visualized with a Mohr solution (10 g FeSO4 in 100 mL of
Computational Methods: Owing to their excellent performance-to-
H2O). Kieselgel 60, 230–400 mesh (Merck), or neutral alumina was cost ratio, the DFT methods constitute a very appealing approach,
2162
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2156–2166

Functionalized 2,5-Dipyridinylpyrroles by Electrochemical Reduction
and new hybrid functionals were developed that include kinetic en-
ergy density. The recent MPWB1K functional set up by Truhlar
and coworkers[32] proved to outperform the popular B3LYP func-
tional for energy-barrier prediction for kinetics, among others.[32–35]
In the present work, we thus selected the MPWB1K functional in
conjunction with the 6-31+G(d,p) basis set to establish the confor-
mational profile of 2,5-dipyridin-2-ylpyrrole 18. The harmonic fre-
quencies were computed to characterize the stationary points (min-
ima vs. TSs) and to estimate the zero-point vibrational energy
(ZPVE) corrections and thermodynamic parameters. The popula-
tion of the various conformers was evaluated from the computed
Gibbs energies through a Boltzmann distribution according to the
relation:
from tetrazine 6 (236 mg) and 3-butyn-1-ol (286 mg) in toluene.
Yellow powder. M.p. 64 °C (ref.[20] 65–66 °C).
4-Ethoxy-3,6-dipyridin-2-ylpyridazine (12): Compound 12 was syn-
thesized following General Procedure B from tetrazine 6 (430 mg)
and ethyl ethynyl ether (256 mg) in toluene (5 mL; 60 °C, 5 d). Af-
ter purification (DCM/petroleum ether, 8:2), pyridazine 12 was iso-
1
lated in 40% yield (203 mg). Pale-orange crystals. M.p. 141 °C. H
NMR (300 MHz, CDCl3): δ = 8.77–8.68 (m, 3 H, Hpyridine), 8.13
(s, 1 H, Hpyridazine), 7.95–7.81 (m, 3 H, Hpyridine), 7.40–7.34 (m, 2
H, Hpyridine), 4.25 (q, J = 7.02 Hz, 2 H, OCH2), 1.47 (t, J = 6.99 Hz,
3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.1, 157.1,
153.9, 153.5, 152.0, 149.3, 149.3, 137.3, 136.5, 125.1, 124.9, 123.7,
122.2, 106.2, 64.7, 14.3 ppm. MS: m/z (%) = 278 (88) [M]+, 263
(62) [M – CH3]+, 234 (22) [M – OEt]+, 205 (100) [M – OEt +
N2]+, 78 (54) [C5H4N]+. HRMS (ESI+): calcd. for C16H15N4O [M
+ H]+ 279.1240; found 279.1245.
4-Ethoxycarbonyl-3,6-dipyridin-2-ylpyridazine (13): Compound 13
was synthesized following General Procedure B from tetrazine 6
(400 mg) and ethyl propiolate (345 µL) in toluene (20 mL; 110 °C,
4 d). Pyridazine 13 was isolated, after purification by flash
chromatography (ethyl acetate/petroleum ether, 3:7), in 82% yield
(425 mg). Yellowish powder. M.p. 101 °C (ref.[21] 100 °C).
The studied compound is likely to show stable conformations in-
cluding intramolecular interactions, and the estimation of the intra-
molecular basis set superposition error (BSSE) is well known to be
a difficult task. It is therefore almost always ignored in the calcula-
tions.[36] Consequently, single-point calculations were carried out at
the LMP2/6-311++G(d,p)//MPWB1K/6-31+G(d,p) level of theory,
as the local MP2 (LMP2) method greatly reduces the BSSE contri-
bution.[37]
3,6-Dipyridin-4-ylpyridazine (14): Compound 14 was prepared ac-
cording to General Procedure B from tetrazine 7 (236 mg) and ethyl
vinyl ether (145 mg) in dioxane (reflux, 4 h). Pyridazine 14 was iso-
lated in 93% yield (218 mg) by filtration after cooling the reaction
All gas phase calculations were performed by using the Gaussian
03[38] and Jaguar[39] packages.
1
mixture. Pink powder. M.p. 230 °C. H NMR (300 MHz, CDCl3):
δ = 8.07 (s, 2 H, Hpyridazine), 8.08–8.04 (m, 4 H, Hpyridine), 8.86–8.83
(m, 4 H, Hpyridine) ppm. 13C NMR (75 MHz, CDCl3): δ = 156.7,
150.8; 142.8, 124.6, 120.9 ppm. HRMS (ESI+): calcd. for C14H11N4
[M + H]+ 235.0984; found 235.0986.
3,6-Dipyridin-2-yl-1,2,4,5-tetrazine (6): Compound 6 was synthe-
sized following General Procedure A[40] in 92% yield (3.16 g) from
2-cyanopyridin-2-yl (3.0 g). Purple powder. M.p. 227 °C (ref.[19,20]
229–230 °C).
3,6-Bis(6-methylpyridin-2-yl)pyridazine (15): Compound 15 was
synthesized by following General Procedure B from tetrazine 8
(3.17 g) and ethyl vinyl ether (1.75 g) in 1,4-dioxane (120 mL; re-
flux, 90 min). Pyridazine 15 was isolated in 98% yield (3.08 g) by
filtration after cooling the reaction mixture. Yellowish powder.
M.p. 148 °C. 1H NMR (300 MHz, CDCl3): δ = 8.69 (s, 2 H,
3,6-Dipyridin-4-yl-1,2,4,5-tetrazine (7): Compound 7 was synthe-
sized following General Procedure A in 69% yield (3.3 g) from 2-
cyanopyridin-4-yl (4.2 g). Purple powder. M.p. 254 °C (decomp.)
1
[ref.[41] 258 °C (decomp.)]. H NMR (300 MHz, CDCl3): δ = 8.96
(dd, J = 1.7, 4.7 Hz, 4 H), 8.45 (d, J = 1.7, 4.6 Hz, 4 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 163.7, 151.4, 138.7, 121.6 ppm. NMR
was in accordance with the literature data.[42]
Hpyridazine), 8.57–8.54 (d, J = 8.0 Hz, 2 H, Hpyridine), 7.81–7.76 (t, J
= 7.8 Hz, 2 H, Hpyridine), 7.28–7.25 (d, J = 7.6 Hz, 2 H, Hpyridine),
2.67 (s, 6 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 158.3,
137.3, 125.0, 124.2, 118.7, 24.6 ppm. MS: m/z (%) = 262 (39)
[M]+, 233 (48) [M – N2 + H]+, 142 (62) [M – N2 + C6H6N]+, 92
(54) [C6H6N]+. HRMS (EI): calcd. for C16H14N4 262.1219; found
262.1211.
3,6-Bis(6-methylpyridin-2-yl)-1,2,4,5-tetrazine (8): Compound 8 was
synthesized according to General Procedure A in 65% yield (3.4 g)
from 2-cyano-6-methylpyridin-2-yl (4.8 g). Purple powder. M.p.
229 °C. 1H NMR (300 MHz, CDCl3): δ = 8.55–8.52 (d, J = 7.7 Hz,
2 H, Hpyridine), 7,91–7.86 (t, J = 7.8 Hz, 2 H, Hpyridine), 7,45–7.43
(d, J = 7.8 Hz, 2 H, Hpyridine), 2.79 (s, 6 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 163.9, 160.2, 149.6, 137.5, 126.4, 121.8,
24.8 ppm. MS: m/z (%) = 265 (100) [M]+. HRMS (ESI+): calcd.
for C14H13N6 [M + H]+ 265.1202; found 265.1207
4-Butyl-3,6-bis(6-methylpyridin-2-yl)pyridazine (16): Compound 16
was synthesized by following General Procedure B from tetrazine
8 (444 mg) and hex-1-yne (790 µL) in DMF (30 mL; 80 °C, 48 h).
Pyridazine 16 was isolated in 84% yield (449 mg) after purification
by flash chromatography (petroleum ether/ethyl acetate, 8:2). Yel-
3,6-Dipyridin-2-ylpyridazine (9): Compound 9 was synthesized in
92% yield (215 mg) according to the literature and by following
General Procedure B from tetrazine 6 (236 mg) and ethyl vinyl
ether (145 mg) in dioxane (reflux, 90 min). Pyridazine 9 was iso-
lated by filtration after cooling the reaction mixture. Yellowish
powder. M.p. 178–179 °C (ref.[20,43] 178–180 °C).
1
lowish oil. H NMR (300 MHz, [D6]DMSO): δ = 8.42–8.39 (m, 2
H, Hpyridine, Hpyridazine), 7.94–7.88 (m, 2 H, Hpyridine), 7.80–7.74 (d,
J = 7.8 Hz, 1 H, Hpyridine), 7.44–7.39 (t, J = 7.6 Hz, 2 H, Hpyridine),
3.02–2.95 (t, J = 6.8 Hz, 2 H, CH2butyl), 2.61 (s, 3 H, CH3pyridine),
2.56 (s, 3 H, CH3pyridine), 1.58–1.47 (m, 2 H, CH2butyl), 1.35–1.21
(m, 2 H, CH2butyl), 0.85–0.77 (t, J = 7.0 Hz, 3 H, CH3butyl) ppm.
13C NMR (75 MHz, DMSO): δ = 158.9, 158.1, 156.9, 155.1, 152.1,
142.0, 137.8, 137.4, 125.0, 124.5, 123.1, 121.4, 118.2, 31.8, 31.4,
24.2, 24.0, 22.0, 13.5 ppm. MS: m/z (%) = 318 (54) [M]+, 289 (100)
[M – N2 + H]+, 92 (12) [C6H6N]+. HRMS (ESI+): calcd. for
C20H23N4 319.1923; found 319.1923.
4-Butyl-3,6-dipyridin-2-ylpyridazine (10): Compound 10 was pre-
pared in 91% yield (559 mg) according to the literature and by
following General Procedure B from tetrazine 6 (500 mg) and
hexyne (350 mg) in DMF (60 °C, 2 d). Yellowish powder. M.p. 71–
72 °C (ref.[20] 70–71 °C).
4-(1-Hydroxyethyl)-3,6-dipyridin-2-ylpyridazine (11): Compound 11
4-Ethoxycarbonyl-3,6-bis(6-methylpyridin-2-yl)pyridazine
(17):
was prepared in 71% yield (197 mg) according to the literature
Compound 17 was synthesized following General Procedure B
Eur. J. Org. Chem. 2008, 2156–2166
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2163

D. Dubreuil et al.
FULL PAPER
from tetrazine 8 (500 mg) and ethyl propiolate (640 µL) in toluene
(20 mL; 110 °C, 48 h). Pyridazine 17 was isolated in 97% yield
(614 mg) after purification by flash chromatography (petroleum
ether/ethyl acetate, 7:3). Pink powder. M.p. 166 °C. 1H NMR
J = 4.3 Hz, 1 H, Hpyridine), 8.47 (br. d, J = 4.3 Hz, 1 H, Hpyridine),
7.95 (d, J = 8.1 Hz, 1 H, Hpyridine), 7.63–7.57 (m, 2 H, Hpyridine),
7.47 (d, J = 8.1 Hz, 1 H, Hpyridine), 7.05–6.95 (m, 2 H, Hpyridine),
6.45 (br. s, 1 H, Hpyrrole), 4.15 (q, J = 6.9 Hz, 2 H, OCH2), 1.48 (t,
(300 MHz, CDCl3): δ = 8.74 (s, 1 H, Hpyridazine), 8.54 (d, J = 7.8 Hz, J = 6.9 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
1 H, Hpyridine), 8.34 (d, J = 7.9 Hz, 1 H, Hpyridine), 7.82–7.76 (m, 2 149.7, 149.1, 148.6, 148.0, 136.2, 136.2, 120.8, 119.5, 119.4, 118.0,
H, Hpyridine), 7.29–7.24 (m, 2 H, H pyridine), 4.43–4.36 (q, J =
108.9, 95.6, 66.5, 15.2 ppm. HRMS (ESI+): calcd. for C16H16N3O
7.2 Hz, 2 H, CH2ethoxycarbonyl), 2.66–2.58 (s, 6 H, CH3pyridine), 1.36– [M + H]+ 266.1293; found 266.1293.
1.33 (t, J = 7.2 Hz, 3 H, CH3ethoxycarbonyl) ppm. 13C NMR
When the reduction of pyridazine 12 was performed at the poten-
tial of the first peak reduction (E = –0.95 V/ECS, 6.5 h), the corre-
sponding pyrrole 21 was obtained in 70% yield.
(75 MHz, CDCl3): δ = 166.9, 157.8, 157.5, 156.7, 151.9, 151.2,
136.6, 131.6, 123.9, 123.3, 122.8, 119.3, 118.0, 61.2, 23.8, 23.5,
13.3 ppm. MS: m/z (%) = 334 (7) [M]+, 305 (8) [M – N2 + H]+, 233
(39) [M – N2 + COOEt]+, 142 (27) [M – N2 + CO2Et + C6H6N +
3-Ethoxycarbonyl-2,5-dipyridin-2-ylpyrrole (22): Compound 22 was
obtained in 53% yield (102 mg) by electrochemical reduction (E =
H]+, 92 (51) [C H N]+. IR: ν = 1727 (C=O) cm–1. HRMS (EI):
˜
6
6
1
–1.00 V/ECS, 6.2 h) of pyridazine 13 (201 mg). Yellow powder. H
calcd. for C19H18N4O2 334.1430; found 334.1421.
NMR (300 MHz, CDCl3): δ = 10.13 (br. s, 1 H, NH), 8.70 (d, J =
8.1 Hz, 1 H, Hpyridine), 8.53 (br. d, J = 4.8 Hz, 1 H, Hpyridine), 8.46
(br. d, J = 4.8 Hz, 1 H, Hpyridine), 7.69–7.63 (m, 2 H, Hpyridine),
7.57–7.55 (m, 1 H, Hpyridine), 7.18 (d, J = 2.2 Hz, 1 H, Hpyrrole),
7.16–7.03 (m, 2 H, Hpyridine), 4.29 (q, J = 7.1 Hz, 2 H, OCH2), 1.31
(t, J = 7.1 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
165.1, 149.4, 148.8, 149.3, 148.9, 136.7, 136.6, 135.6, 131.2, 123.5,
122.6, 121.6, 118.7, 115.0, 111.9, 60.3, 14.5 ppm. HRMS (ESI+):
calcd. for C17H16N3O3 [M + H]+ 294.1243; found 294.1246.
2,5-Dipyridin-2-ylpyrrole (18): Compound 18 was obtained in 82%
yield (167 mg) by electrochemical reduction (E = –1.05 V/ECS,
4.6 h) of pyridazine 9 (215 mg). Yellow crystals. M.p. 91 °C. 1H
NMR (300 MHz, CDCl3): δ = 10.52 (br. s, 1 H, NH), 8.53–8.49
(m, 2 H, Hpyridine), 7.65–7.52 (m, 4 H, Hpyridine), 7.07–7.00 (m, 2
H, Hpyridine), 6.75 (d, J = 2.1 Hz, 2 H, 2Hpyrrole) ppm. 13C NMR
(75 MHz, CDCl3): δ = 150.1, 133.1, 149.1, 136.2, 120.7, 118.3,
108.8 ppm. MS: m/z (%) = 221 (22) [M]+, 220 (100) [M – 1]+.
HRMS (ESI+): calcd. for C14H12N3 [M + H]+ 222.1031; found
222.1033.
2,5-Dipyridin-4-ylpyrrole (23): Compound 23 was obtained in 85%
yield (169 mg) by electrochemical reduction (E = –1.00 V/ECS, 4 h)
of pyridazine 14 (210 mg). Yellowish crystals. M.p. 261 °C. 1H
NMR (300 MHz, [D6]DMSO): δ = 11.81 (br. s, 1 H, NH), 8.57–
8.54 (m, 1 H, Hpyridine), 7.79–7.77 (m, 4 H, Hpyridine), 6.97 (d, J =
2.1 Hz, 2 H, 2Hpyrrole) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
149.3, 145.5, 136.7, 133.1, 120.7, 118.9, 99.3 ppm. HRMS (ESI+):
When the reduction of pyridazine 9 was performed at the potential
of the first peak reduction (E = –0.85 V/ECS, 7 h), the correspond-
ing pyrrole 18 was obtained in 72% yield.
3-Butyl-2,5-dipyridin-2-ylpyrrole (19): Compound 19 was obtained
in 87% yield (173 mg) by electrochemical reduction (E = –1.08 V/
ECS, 6 h) of pyridazine 10 (207 mg). Yellow powder. 1H NMR calcd. for C14H12N3 [M + H]+ 222.1031; found 222.1030.
(300 MHz, CDCl3): δ = 10.48 (br. s, 1 H, NH), 8.52 (br. d, J =
3,6-Bis(6-methylpyridin-2-yl)pyrrole (24): Compound 24 was ob-
4.8 Hz, 1 H, Hpyridine), 8.56 (br. d, J = 4.8 Hz, 1 H, Hpyridine), 7.69–
tained in 77% yield (135 mg) by electrochemical reduction (E =
7.51 (m, 4 H, Hpyridine), 7.07–7.01 (m, 2 H, Hpyridine), 6.64 (d, J =
–1.05 V/ECS, 3.2 h) of pyridazine 15 (184 mg). Yellow powder.
2.8 Hz, 1 H, Hpyrrole), 2.82 (t, J = 7.9 Hz, 2 H, CH2), 1.71 (m, 2
M.p. 96 °C. 1H NMR (300 MHz, CDCl3): δ = 10.9 (br. s, 1 H,
H, CH2), 1.52 (m, 2 H, CH2), 0.98 (t, J = 7.3 Hz, 3 H, CH3) ppm.
NHpyrrole), 7.54–7.43 (m, 4 H, Hpyridine), 6.90–6.87 (d, J = 7.4 Hz, 2 H,
13C NMR (75 MHz, CDCl3): δ = 150.8, 150.2, 149.4, 149.2, 136.3,
H
pyridine), 6.74 (s, 2 H, Hpyrrole), 2.56 (s, 6 H, H3) ppm. 13C NMR
136.3, 131.3, 128.7, 126.12, 120.7, 120.3, 119.3, 118.4, 110.2, 32.5,
27.7, 22.8, 14.8 ppm. MS: m/z (%) = 277 (73) [M]+, 248 (100) [M –
C2H5]+, 234 (64) [M – CH2]+, 155 (8) [M – C5H4N]+, 78 (21)
[C5H4N]+. HRMS (ESI+): calcd. for C18H20N3 [M + H]+ 278.1657;
found 278.1654.
(75 MHz, CDCl3): δ = 156.0, 148.6, 137.7, 120.6, 116.3, 110.7,
23.7 ppm. MS: m/z (%) = 249 (100) [M]+, 92 (18) [C H N]+. IR: ν
˜
6
6
= 3443 (NH) cm–1. HRMS (ESI+): calcd. for C16H16N3 250.1344;
found 250.1344.
4-Butyl-3,6-bis(6-methylpyridin-2-yl)pyrrole (25): Compound 25
was obtained in 72% yield (147 mg) by electrochemical reduction
(E = –1.05 V/ECS, 4.2 h) of pyridazine 16 (204 mg). Yellow powder.
M.p. 93 °C. 1H NMR (300 MHz, CDCl3): δ = 11.9 (br. s, 1 H,
NHpyrrole), 7.89–7.85 (m, 3 H, Hpyridine), 7.67–7.64 (d, J = 7.9 Hz,
1 H, Hpyridine), 7.23–7.21 (m, 2 H, Hpyridine), 7.02 (s, 1 H, Hpyrrole),
2.89–2.84 (t, J = 7.8 Hz, 2 H, CH2butyl), 2.65 (s, 3 H, CH3pyridine),
2.62 (s, 3 H, CH3pyridine), 1.71–1.64 (quint., J = 7.8 Hz, 2 H,
CH2butyl), 1.50–1.45 (sext., J = 7.2 Hz, 2 H, CH2butyl), 1.01–0.97 (t,
When the reduction of pyridazine 10 was performed at the poten-
tial of the first peak reduction (E = –0.85 V/ECS, 7 h), the corre-
sponding pyrrole 19 was obtained in 78% yield.
3-(1-Hydroxyethyl)-2,5-dipyridin-2-ylpyrrole (20): Compound 20
was obtained in 92% yield (158 mg) by electrochemical reduction
(E = –1.10 V/ECS, 5.3 h) of pyridazine 11 (202 mg). Yellow powder.
1H NMR (300 MHz, CDCl3): δ = 10.33 (br. s, 1 H, NH), 8.48 (br.
d, J = 4.8 Hz, 1 H, Hpyridine), 8.45 (br. d, J = 4.8 Hz, 1 H, Hpyridine),
7.67–7.61 (m, 2 H, Hpyridine), 7.59–7.50 (m, 2 H, Hpyridine), 7.10– J = 7.1 Hz, 3 H, CH3butyl) ppm. 13C NMR (75 MHz, CDCl3): δ =
7.01 (m, 2 H, Hpyridine), 6.64 (br. s, 1 H, Hpyrrole), 3.99 (t, J = 5.9 Hz, 170.1, 156.9, 149.0, 126.5, 121.0, 120.6, 117.4, 116.5, 112.8, 32.1,
2 H, CH2), 3.06 (t, J = 5.9 Hz, 2 H, CH2) ppm. 13C NMR
26.6, 23.7, 22.8, 22.1, 13.8 ppm. MS: m/z (%) = 305 (45) [M]+, 92
(75 MHz, CDCl3): δ = 150.5, 149.9, 149.0, 148.8, 137.1, 136.6, (46) [C H N]+. IR: ν = 3432 (NH) cm–1. HRMS (ESI+): calcd. for
˜
6
6
132.2, 130.1, 123.3, 120.9, 119.8, 118.7, 110.9, 64.0, 30.4 ppm.
HRMS (ESI+): calcd. for C16H16N3O [M + H]+ 266.1293; found
266.1291.
C20H24N3 306.1970; found 306.1973.
4-Ethoxycarbonyl-3,6-bis(6-methylpyridin-2-yl)pyrrole (26): Com-
pound 26 was obtained in 37% yield (84 mg) by electrochemical
reduction (E = –1.05 V/ECS, 9 h) of pyridazine 16 (225 mg). Yellow
3-Ethoxy-2,5-dipyridin-2-ylpyrrole (21): Compound 21 was ob-
tained in 68% yield (126 mg) by electrochemical reduction (E =
1
powder. M.p. 92 °C. H NMR (300 MHz, CDCl3): δ = 10.9 (br. s,
1
–1.18 V/ECS, 5.2 h) of pyridazine 12 (194 mg). Yellow powder. H
1 H, NHpyrrole), 8.49–8.46 (d, J = 8.1 Hz, 1 H, Hpyridine), 7.57–7.47
(m, 2 H, Hpyridine), 7.38–7.35 (d, J = 8.0 Hz, 1 H, Hpyridine), 7.14
NMR (300 MHz, CDCl3): δ = 10.23 (br. s, 1 H, NH), 8.50 (br. d,
2164
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2156–2166

Functionalized 2,5-Dipyridinylpyrroles by Electrochemical Reduction
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nik, CNRS Patent, FR 06 06841, 2006.
(s, 1 H, Hpyrrole), 7.01–6.99 (d, 1 H, Hpyridine), 6.90–6.93 (d,
J = 7.5 Hz, 1 H, Hpyridine), 4.29–4.24 (q, J = 7.1 Hz, 2 H,
CH2ethoxycarbonyl), 2.55 (s,
3 H, CH3pyridine), 2.52 (s, 3 H,
CH3pyridine), 1.36–1.30 (t, J = 7.1 Hz, 3 H, CH3ethoxycarbonyl) ppm.
13C NMR (75 MHz, CDCl3): δ = 165.0, 158.0, 157.5, 148.7, 136.8,
136.7, 131.2, 122.1, 120.9, 120.6, 115.6, 114.6, 111.5, 60.1, 24.5,
14.4 ppm. MS: m/z (%) = 321 (62) [M]+, 275 (100) [M – EtOH]+,
249 (24) [M – COOEt + H]+, 92 (46) [C H N]+. IR: ν = 3426 (NH),
˜
6
6
1698 (C=O). HRMS (ESI+): calcd. for C19H20N3O2 322.1556;
found 322.1555.
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2000, 39, 585–590.
When the reduction of pyridazine 16 was performed at the poten-
tial of the first peak reduction (E = –0.70 V/ECS, 4 h), the corre-
sponding pyrrole 26 was not obtained.
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4-Ethoxy-1,6-dihydro-3,6-dipyridin-2-ylpyridazine (27): Compound
27 was obtained as a side product in only 12% yield (19 mg) by
electrochemical reduction of pyridazine 12 (176 mg) at the first re-
duction peak potential (E = –0.95 V/ECS, 6.5 h). Orange oil. 1H
NMR (300 MHz, CDCl3): δ = 8.59–8.51 (m, 2 H, Hpyridine), 7.96–
7.90 (m, 1 H, Hpyridine), 7.62–7.55 (m, 2 H, Hpyridine), 7.30–7.27 (d,
J = 7.9 Hz, 1 H, Hpyridine),7.16–7.13 (m, 2 H, Hpyridine), 7.01 (br. s,
1 H, NH), 6.43 (s, 1 H, Hpyridazine), 4.92 (s, 1 H, Hdihydropyridazine),
4.22–4.14 (q, J = 7.1 Hz, 2 H, CH2), 1.40–1.36 (t, J = 6.9 Hz, 3 H,
CH3) ppm.
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R. Hoogenboom, G. Kickelbick, U. S. Schubert, Eur. J. Org.
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[25] C14H11N3: The data set was collected with a Nonius-Bruker
Kappa CCD diffractometer by using Mo-KL2,3 radiation.
C14H11N3 (M = 221.3): orthorhombic, space group Pbcn,
Dcalcd. = 1.333 gcm–3, a = 10.8412(12) Å, b = 11.538(2) Å, c =
17.6275(11) Å, V = 2204.9(5) Å3, Z = 8, λ = 0.71069 Å, µ =
0.082 mm–1, T = 100 K, R(F2) = 0.0652 for 2474 observed re-
flections [I Ͼ 2σ(I)] and Rw(F2) = 0.1391 for all 3152 reflec-
tions. CCDC-648306.
4-Ethoxycarbonyl-1,4-dihydro-3,6-dipyridin-2-ylpyridazine
(28):
Compound 28 was obtained in 75% yield (161 mg) by electrochem-
ical reduction of pyridazine 13 (214 mg) at the first reduction peak
potential (E
=
–0.70 V/ECS, 4.1 h). Yellow oil. 1H NMR
(300 MHz,CDCl3):δ=10.64(s,1H,NH),8.67–8.74(m,2H,Hpyridine),
8.08–8.11 (d, J = 8.0 Hz, 1 H, Hpyridine), 7.88–7.94 (m, 2 H,
Hpyridine), 7.46–7.56 (m, 3 H, Hpyridine), 3.84–3.91 (q, J = 7.0 Hz, 2
H, CH2ethoxycarbonyl), 3.65 (s, 2 H, CH2dihydropyridazine), 0.86–0.91 (t,
J = 7.1 Hz, 3 H, CH3ethoxycarbonyl) ppm. IR: ν = 3414 (NH), 1683
˜
(C=O) cm–1.
CCDC-648305 (for 23) and -648306 (for 18) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[26] C14H11N3·H2O: The data set was collected with a Nonius-
Bruker Kappa CCD diffractometer by using Mo-KL2,3 radia-
tion. C14H13N3O (M = 239.3): orthorhombic, space group
P212121, Dcalcd.
= a = 5.6859(5) Å, b =
1.287 gcm–3,
8.0090(5) Å, c = 27.1194(16) Å, V = 1234.97(15) Å3, Z = 4, λ
= 0.71069 Å, µ = 0.084 mm–1, T = 120 K, R(F2) = 0.0471 for
4698 observed reflections [I Ͼ 2σ(I)] and Rw(F2) = 0.1141 for
all 5212 reflections. CCDC-698305.
Acknowledgments
The authors gratefully acknowledge the CCIPL (Centre de Calcul
Intensif des Pays de la Loire), the CINES (Centre Informatique
National de l’Enseignement Supérieur), and the IDRIS (Institut
Des Ressources en Informatique Scientifique) for computer time.
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2165

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Received: November 26, 2007
Published Online: March 13, 2008
(since its publication in Early View, a minor change
in one of the co-authors’ names has been made.)
2166
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2156–2166