Activated pyrroles from pyridazines: Nitrogen extrusion by electroreduction

Article abstract of DOI:10.1016/S0040-4039(99)02155-3

The bielectronic electrochemical reduction of pyridazines, substituted by electron-withdrawing groups, leads to their corresponding 1,2-dihydro derivatives. Depending on the nature of the ring substitution, these intermediates can either rearrange into 1,

Full text of DOI:10.1016/S0040-4039(99)02155-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 647–650
Activated pyrroles from pyridazines: nitrogen extrusion by
electroreduction
G. T. Manh,a R. Hazard,b J. P. Pradère,a,∗ A. Tallec,b E. Raoult b and D. Dubreuil a
aLaboratoire de Synthèse Organique, UMR No. 6513, Faculté des Sciences et des Techniques, 2 rue de la Houssinière,
44322 Nantes Cedex 3, France
bLaboratoire de Chimie et d’Électrochimie Organiques, UMR No. 6510, Université de Rennes I -Beaulieu,
35042 Rennes Cedex, France
Received 15 July 1999; accepted 12 November 1999
Abstract
The bielectronic electrochemical reduction of pyridazines, substituted by electron-withdrawing groups, leads to
their corresponding 1,2-dihydro derivatives. Depending on the nature of the ring substitution, these intermediates
can either rearrange into 1,4-dihydropyridazine isomers or be further electrochemically reduced into activated
pyrroles. © 2000 Published by Elsevier Science Ltd. All rights reserved.
Keywords: electrochemical reduction; pyridazine; ring contraction; dihydropyridazine; pyrrole; nitrogen extrusion.
Ring transformation of heterocycles appears to be an efficient methodology to produce pyrrole
derivatives.1 We have previously shown that substituted pyrroles can be obtained by sulfur extrusion
from 1,3-thiazine heterocycles2 by an electrochemical reduction process.3,4 In particular, functionalized
pyrroles 2 were isolated from the 4H-1,3-thiazines 1 following this procedure (Scheme 1).5,6
Scheme 1.
The presence of the heterocyclic nitrogen atom is crucial for the above extrusion process to be
achieved since no ring contraction occurred in the same conditions from 4H-thiopyran analogues.7
Nitrogen extrusion from six membered azaheterocycles has also been investigated as an attractive way to
produce substituted pyrroles.1 Although reductive ring contraction of activated pyridazine derivatives was
successfully performed by chemical reduction,8,9 only a few studies using electrochemical procedures
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02155-3
tetl 16083

648
have been reported. In the latter approach, a mixture of two pyrroles 4 was obtained by Lund from the
pyridazinium cation 3 (Scheme 2).10,11
Scheme 2.
Taking into account these results, we proceeded to evaluate the potential of activated pyridazines 5 to
give the corresponding functionalized pyrroles by an electrochemical reduction process (retrosynthesis).
Substituted pyridazines 5a–5c were first prepared by a convergent synthesis from 1,2,4,5-tetrazine-
3,6-dicarboxylic acid dimethyl ester.12 The influence of the nature of the substituent groups on the
electrochemical behavior of the pyridazine precursors has been examined (Scheme 3). The polarographic
experiments and the preparative electrolysis were performed in acetate buffer.13
Scheme 3.
(a) Pyridazine-3,6-dicarboxylic acid dimethyl ester 5a14 is reducible in three successive bielectronic
steps (E1/2=−0.69; −0.86 and −1.07 V/SCE). Preparative electrolysis, carried out under nitrogen
atmosphere at the potential of the first wave, leads quantitatively to the 1,4-dihydropyridazine derivative
6a, which can be further reduced at the level of the third wave. Controlled potential reduction (CPR)
at the plateau of the second wave (E=−1.0 V/SCE) gives rise to the formation of the 1H-pyrrole-2,5-
dicarboxylic acid dimethyl ester 7a,15–17 in 60% yield, beside some starting material 5a resulting from
air oxidation of the 1,4-dihydro derivative 6a during the reaction work up (Scheme 3).
(b) Pyridazine-3,4,5,6-tetracarboxylic acid tetramethyl ester 5b14 shows only two bielectronic reduc-
tion waves at E1/2=−0.45 and −1.05 V/SCE (to be compared with the first and the third waves for com-

649
pound 5a). The electroreduction at −0.7 V/SCE yields quantitatively the 1,4-dihydropyridazine-3,4,5,6-
tetracarboxylic acid tetramethyl ester 6b18 (Scheme 3). This compound appears to be further reducible at
a more negative potential. However, the corresponding 1H-pyrrole derivative 7b was not obtained. Due
to our objective, focused on possible access to pyrroles 7, reduction of the 1,4-dihydropyridazines 6 has
not been investigated.
(c) Polarographic reduction of the 4-phenyl-pyridazine-3,6-dicarboxylic acid dimethyl ester 5c14
displays three successive waves at E1/2=−0.72 (higher than a two electron reduction wave); −0.86 (lower
than a two electron wave) and −1.03 V/SCE (corresponding to a bielectronic process). Such a behavior
clearly indicates a disproportionation of the two electron reduction product (vide infra). However, the
preparative electrolysis, carried out in the range of −0.7 to −0.9 V/SCE, always leads to a mixture of
the corresponding 1,4-dihydropyridazine 6c19 and 3-phenyl-1H-pyrrole-2,5-dicarboxylic acid dimethyl
ester 7c9,17(Scheme 3). The best yield (70%) in pyrrole is obtained at more negative potential (−0.9
V/SCE). This result can be compared with the chemical reduction path (zinc in acidic medium), yielding
the pyrrole 7c at 65%.12
As a conclusion, electroreduction of pyridazines 5 is governed by the chemical behavior of the 1,2-
dihydro intermediate, resulting from the two electron reduction process: (i) if the rearrangement of
the 1,2-dihydro intermediate into the corresponding 1,4-isomer derivative (series b) is very fast, the
formation of pyrrole 7 is not observed; (ii) if this rearrangement is slow enough (series a), pyrrole
can be formed when electroreduction is performed at the plateau of the second polarographic wave;
(iii) however, disproportionation of the 1,2-dihydropyridazine remains possible (series c) leading to
an equimolecular mixture of pyrrole 7c and starting compound 5c (Scheme 4).This reaction is thus in
competition with the prototropy event giving the dihydropyridazine 6c
Scheme 4.
Such an interpretation must be correlated with complementary investigations which should be run from
other pyridazine precursors. In particular, experiments from pyridazine-3,6-dicarboxylic acid dimethyl
ester derivatives carrying electron-donating substituents at the 4 and/or 5 position must be investigated.
However, we have already demonstrated the possibility of formation of functionalized 1H-pyrroles
by electrochemical reduction of activated pyridazines. Thus, nitrogen extrusion from pyridazine-3,6-
dicarboxylic acid dimethyl ester through an electroreduction process leads to substituted 1H-pyrrole 7c,
a structural isomer of the 1H-pyrrole 2 (R=H).
Acknowledgements
This work was partially supported by a Grant-in-Aid for Scientific Research from the Ministry of
National Education (Ivory Coast).

650
References
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13. For a typical procedure see Ref. 6. Controlled potential electrolysis is carried out at a mercury pool cathode.
14. For the synthesis of pyridazines 5a, 5b and 5c see, respectively: (a) Sauer, J.; Mielert, A.; Lang, D.; Peter, D. Chem. Ber.
1965, 1435–1445. (b) Neunhoeffer, H.; Werner, G. Liebigs Ann. Chem. 1973, 437–442. (c) Ref. 12.
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17. 1H-Pyrrole derivatives 7a15,16 and 7c9 exhibited spectroscopic data (1H NMR, IR, MS) and combustion analyses in
agreement with the structures assigned. Selected data for 7a: 13C NMR (50.3 MHz, CDCl3) δ ppm 51.9 (q, J=147 Hz,
CO2CH3), 115.5 (d, J=177 Hz, C-3, C-4), 126.0 (C-2, C-5), 160.7 (CO2CH3). For 7c: 13C NMR (50.3 MHz, CDCl3) δ ppm
51.5 and 51.8 (J=147 Hz, CO2CH3), 116.5 (J=170 Hz, C-4), 127.2, 127.6, 129.1 and 132.2 (Ph), 121.0, 124.5 and 133.7
(C-5, C-3 and C-2), 160.5 (CO2CH3).
18. 1,4-Dihydropyridazine-3,4,5,6-tetracarboxylic acid tetramethyl ester 6b: m.p.=126–127°C (from petroleum ether). 1H
NMR (200 MHz, CDCl3) δ ppm 3.7 and 3.8 (2s, 6H, OCH3), 3.9 (1s, 6H, OCH3), 5.02 (s, 1H, CH), 9.26 (s, 1H, NH);
13C NMR (50.3 MHz, CDCl3) δ ppm 36.9 (d, J=140 Hz, C-4), 52.2, 52.7, 52.9 and 53.3 (4q, J=148 Hz, OCH3), 98.0,
132.1 and 136.9 (C-3, C-5 and C-6), 162.8, 163.4, 164.8 and 169.0 (CO2CH3). νmax cm−1: 3275, 3225, 1775, 1750, 1640,
1610. MS m/z (%): 314 (CI, M+), 256 (10), 255 (97), 224 (11), 223 (100), 167 (12), 137 (10), 59 (22). Elemental analysis:
C12H14N2O8; calcd: C, 45.87; H, 4.49; N, 8.91; found: C, 45.84; H, 4.48; N, 8.83.
19. For chemical synthesis of 4-phenyl-1,4-dihydropyridazine-3,6-dicarboxylic dimethyl ester 6c see Ref. 14a. Selected data:
13C NMR (50.3 MHz, CDCl3) δ ppm 37.7 (d, J=136 Hz, C-4), 52.7 and 52.9 (2q, J=140 Hz, 2CO2CH3), 110.7 (d, J=173
Hz, C-5), 127.9, 128.1, 128.4, 129.2, 133.0 and 142.7 (Ph, C-3 and C-6), 162.2, 164.9 (CO2CH3).