Electrosynthesis of dibenzonaphthyridine derivatives from 2,2-(2-nitrobenzyl)-2-substituted-acetonitriles

Article abstract of DOI:10.1016/S0040-4039(02)01248-0

An indirect electrochemical procedure involving an ex-cell two-phase process is proposed to produce dibenzonaphthyridine derivatives from 2,2-(2-nitrobenzyl)-2-substituted-acetonitriles in dichloromethane. The selective reduction of both nitro groups into amino groups using Cp₂Ti⁺ in aqueous acidic medium avoids a cyclization of hydroxylamine intermediates as observed by direct electrolysis.

Full text of DOI:10.1016/S0040-4039(02)01248-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5949–5952
Electrosynthesis of dibenzonaphthyridine derivatives from
2,2-(2-nitrobenzyl)-2-substituted-acetonitriles
Thierry Jan, Be´atrice Dupas, Didier Floner and Claude Moinet*
Laboratoire d’Electrochimie et Organome´talliques, UMR CNRS 6509, Institut de Chimie de Rennes, Universite´ de Rennes 1,
Campus de Beaulieu, 35042 Rennes Cedex, France
Received 10 June 2002; accepted 27 June 2002
Abstract—An indirect electrochemical procedure involving an ex-cell two-phase process is proposed to produce dibenzonaph-
thyridine derivatives from 2,2-(2-nitrobenzyl)-2-substituted-acetonitriles in dichloromethane. The selective reduction of both nitro
groups into amino groups using Cp2Ti+ in aqueous acidic medium avoids a cyclization of hydroxylamine intermediates as
observed by direct electrolysis. © 2002 Elsevier Science Ltd. All rights reserved.
Electrochemistry has been currently used to prepare
nitrogen-containing heterocycles from nitro compounds
suitably substituted at the ortho-position.1 It is well
known that two steps leading to nucleophilic centers
are generally observed during direct electrolysis of aro-
matic nitro compounds in acidic media. The first one, a
four-electron reduction, affords hydroxylamines, the
second one, a two-electron reduction, gives amines at a
more cathodic potential. In this paper, we wish to
report a new synthesis of dibenzonaphtyridine deriva-
tives via diamino compounds produced by indirect
electrolysis of easily available 2,2-(2-nitrobenzyl)-2-sub-
stituted-acetonitriles 1a–e.2 To our knowledge, only few
studies about the reduction of similar dinitro com-
pounds have been published. Reissert3 studied the
chemical reduction of 2,2-(2-nitrobenzyl)acetic acid and
observed the formation of a dibenzonaphthyridine
derivative. On the other hand, Leuch and Katinsky4
obtained a spiro compound from the chemical reduc-
tion of 2,2-(2-nitrobenzyl)diethylmalonate.
Polarograms of 1a–c and 1e were performed in acidic
medium (aqueous 2.5 M sulfuric acid–acetone, 1:4 v/v)
and showed two cathodic waves. The first one corre-
sponds to an eight-electron reduction of the two nitro
groups into hydroxylamino groups. The second one,
which corresponds to a four-electron reduction into the
diamino derivatives, is a broad shoulder near the front
of solvent. Cyclic voltammograms (scan rates 0.1 V s−1)
of 1a–c and 1e in the same medium were obtained at a
glassy carbon electrode, and displayed a cathodic peak
corresponding to the formation of hydroxylamino com-
pounds. After potential reverse, an anodic wave
attributed to the oxidation of the two hydroxylamino
groups into the corresponding nitroso groups was only
observed for 1e. The absence of this wave for 1a–c
provided evidence for rapid chemical reactions between
the hydroxylamino functions and the electrophilic
nitrile centers.
Generally, when a macroscale electrolysis of a nitro
aromatic compound is performed in acidic medium, at
a potential close to hydrogen evolution, the whole of
the substrate which is present at the electrode surface is
not totally converted into the corresponding amino
derivative. The intermediate hydroxylamine escapes
from the cathode, so that secondary chemical reactions
can take place in the bulk. Consequently, a selective
reduction of 1a–c into the corresponding diamino
derivatives cannot be realized in a batch-cell fitted with
a mercury or a glassy carbon cathode. Moreover, the
solubility of 1a–e in an aqueous-organic solution is low.
6 Cp2Ti2+ + 6 e
6 Cp2Ti+
6 Cp2Ti2+ + ArNH3+ + 2 H2O
6 Cp2Ti+ + ArNO2 + 7 H+
Scheme 1.
We initially investigated the indirect electrolysis of
nitrobenzenes in organic solvent, using bis-(cyclopenta-
* Corresponding author. Tel.: +33 (0)2 23 23 67 88; fax: +33 (0)2 23
23 59 67; e-mail: claude.moinet@univ-rennes1.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01248-0

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T. Jan et al. / Tetrahedron Letters 43 (2002) 5949–5952
dienyl)titanium cation as mediator in an acidic aqueous
medium, as depicted in Scheme 1.5 Because of a total
selectivity in the reduction of the nitro group into an
amino group, side reactions which occur at the hydroxyl-
amine step were avoided.
(Table 1) and the spirobiquinoline 3f11 were obtained
from 1a–e and from 1f, respectively.
Taken together, these results indicate that several reac-
tions occurred during the indirect electrolysis as shown
in Schemes 2 and 3. One amino group of 2a–d (Scheme
2) reacts with a cyano group giving a fused bicyclic ring
system containing an amidine function. The second
amino group condenses preferentially with the amidine
group affording dibenzonaphthyridines 3a–d with
ammonia elimination. Furthermore, indirect electrolysis
of 1d (entry 4) affects the four nitro groups. Because of
a weaker activation of cyano group in 2e (entry 5), the
primary attack of amino group to cyano group is slow
and a mixture of diamino compound 2e (69%) together
with dibenzonaphthyridine 3e (12%) was isolated after
electrolysis. 3e was obtained as the main product by
heating the mixture in acetic acid.
Typical procedure: 1 g of dinitro compounds 1a–c and
1e–f or tetranitro compound 1d in 200 ml of
dichloromethane in the presence of 0.5 g of titanocene
dichloride dissolved in 200 ml of 1 M sulfuric acid were
added in the flow system used to perform indirect
electrolysis.5a The active form of mediator in aqueous
medium was continuously regenerated at constant cur-
rent intensity (0.15 A) by flowing the aqueous solution
(6 ml mn−1) through a graphite felt cathode until com-
plete disappearance of the starting nitro compound.
After completion of the electrolysis, an aqueous solu-
tion of sodium carbonate was added to the heteroge-
neous mixture until pH>8, then the two phases were
separated. The aqueous solution was extracted with
3×50 ml of dichloromethane and the organic solutions
were combined, dried over magnesium sulfate and
evaporated to dryness. After treatment and purification
of the residue, the dibenzonaphthyridines 3a–e6–10
The unsymmetrical spirobiquinoline 3f results from a
quasi selective primary reaction between amino group
and ester group (Scheme 3). We can note that a by-
product was isolated in a minute quantity (2–3%) by
1
column chromatography. H NMR of this latter is in
Table 1. Indirect electrolysis of 2,2-(2-nitrobenzyl)-2-substituted acetonitrile 1a–e
R2
R2
R2
R2
H
N
R3
NO2 O2N
CN
R3
R4
N
R4
indirect
electrolysis
R1
R1
1a-e
3a-e
Entry
Substrate
No.
Product
R4
Yielda
%
R1
R2
H
R3
1
2
3
4
5
1a
1b
1c
1d
1e
CN
CN
CN
CN
C6H5
H
H
H
H
67
65
70
55
65
CO2CH3
H
H
H
CO2CH3
NO2
H
CO2CH3
NH2
H
a Isolated after column chromatography and based on starting 2-nitrobenzyl bromides.
R2
R2
NH2
NO2
CN
CN
R4
R3
R4
R3
electrolysis
R1
R1
R2
R2
H2N
R2
O2N
2a-e
1a-e
R2
R2
H
N
NH2
H2N
R4
N
R4
R4
N
R2
R4
NH3
R1
R1
3a-e
Scheme 2.

T. Jan et al. / Tetrahedron Letters 43 (2002) 5949–5952
5951
H2N
O2N
CN
CN
electrolysis
CO2CH3
CO2CH3
NH2
NO2
1f
2f
NH2
H2N
N
O
CN
N
H
O
N
H
3f
Scheme 3.
O2N
NHOH
CN
CN
CN
CN
controlled potential
electrolysis
NO2
NHOH
1a
O
N
NH2
H2N
N
O
4a
Scheme 4.
accordance with a dibenzonaphthyridine derivative
resulting from an unfavored primary attack of amino
group to cyano group.
References
1. Lund, H. In Organic Electrochemistry; Lund, H.; Baizer,
M. M., Eds., 3rd ed.; Marcel Dekker: New York, 1991; p.
701.
It is worth noting that the direct electrolysis of 1a in a
mixture of 2.5 M sulfuric acid–acetone (1:4 v/v), at a
mercury cathode maintained at a working potential
corresponding to the first cathodic wave (−0.4 V versus
SCE) afforded the symmetrical spiro compound 4a12
(Scheme 4).
2. The substrates 1a–f were prepared from 2-nitrobenzyl
bromides and, respectively, malonitrile for 1a–d, benzyl
cyanide for 1e and ethyl cyanoacetate for 1f. 1a–e were
obtained by phase transfer catalysis using NBu4HSO4 in
a mixture dichloromethane/2.5 M aqueous NaOH. 1f was
prepared in ethanol containing solid sodium carbonate.
2-Nitrobenzyl bromides were obtained by refluxing
overnight a mixture of 2-nitrotoluenes and N-bromosuc-
cinimide in CCl4 in the presence of catalytic amount of
benzoyl peroxide. The crude substrates 1a–f can be elec-
trochemically reduced without further purification. Physi-
cal data for crystallized (dichloromethane/petroleum
ether) 2,2-(2-nitrobenzyl)-malononitrile (1a): mp 168°C;
1H NMR l (CDCl3) 4.15 (s, 4H), 7.75 (dd, 2H, J=8.2
Hz), 7.85–7.95 (m, 4H), 8.24 (dd, 2H, J=8.2 Hz); 13C
NMR l 39.5, 41.1, 115.6, 126.7, 128.9, 131.3, 134.8,
In conclusion, we reported in this paper an efficient
electrosynthesis of some dibenzonaphthyridine deriva-
tives from readily available 2,2-(2-nitrobenzyl)-2-substi-
tuted acetonitriles. This result is consistent with a
complete reduction of the two nitro groups into amino
groups followed by chemical cyclizations involving only
one nitrile function. However, the method cannot be
used in the presence of an ester substituent at position
2.
134.9, 150.2; IR (KBr) wCN=2245 cm−1, wNO =1545 and
Acknowledgements
2
1344 cm−1. (1e) (Makosza, M.; Jagusztyn-Grochowska, J.
M. Rocz. Chem. 1976, 50, 1859) and (1f) (Reissert, A.
Chem. Ber. 1896, 29, 638) were previously described.
T.J. thanks the MENRT for a grant.

5952
T. Jan et al. / Tetrahedron Letters 43 (2002) 5949–5952
1
3. Reissert, A. Chem. Ber. 1894, 27, 2744.
9. Compound 3d: mp>250°C; H NMR l (CDCl3) 3.00 (s,
4H), 6.07 (dd, 2H, J=7.9 and 2 Hz), 6.16 (d, 2H, J=2
Hz), 6.72 (d, 2H, J=7.9 Hz), 9.95 (s, 1H); 13C NMR l
35.3, 36.3, 108.5, 108.9, 120.6, 126.9, 130.0, 142.3, 149.2,
4. Leuchs, H.; Katinsky, H. V. Chem. Ber. 1922, 55, 710.
5. (a) Floner, D.; Laglaine, L.; Moinet, C. Electrochim. Acta
1997, 42, 523; (b) Moinet, C.; Floner, D.; Jan, T. In
Novel Trends in Electroorganic Synthesis; Torii, S., Ed.;
Kodansha: Tokyo, 1995; p. 177; (c) Jan, T.; Floner, D.;
Moinet, C. Electrochim. Acta 1998, 44, 201.
152.1; IR (KBr) wNH=3220 cm−1
,
wCN=2234 cm−1
MS (m/z) calcd for
,
wNH2=3354 and 3448 cm−1
;
C17H15N5: 289.1317. Found: 289.1340.
1
1
10. Compound 3e: mp 219°C; H NMR l (CDCl3) 3.29 (AB,
6. Compound 3a: mp 218°C; H NMR l (CDCl3) 3.40 (s,
2H, J=15.6 Hz), 3.47 (AB, 2H, J=15.6 Hz), 6.75–7.15
(m, 11H), 7.38 (dd, 2H, J=8.2 and 1.5 Hz), 10.08 (s, 1H);
13C NMR l 40.9, 44.3, 119.1, 122.6, 123.4, 126.2, 127.1,
4H), 6.97 (td, 2H, J=7.4 and 1.3 Hz), 7.03 (dd, 2H, J=8
and 1.1 Hz), 7.18–7.25 (m, 4H), 9.03 (s, 1H); 13C NMR l
36.2, 36.9, 119.7, 120.4, 122.0, 123.8, 128.7, 129.3, 142.4,
152.5; IR (KBr) wNH=3295 cm−1, wCN=2240 cm−1; MS
(m/z) calcd for C17H13N3: 259.1109. Found: 259.1113.
Anal. Calcd: C, 78.74; H, 5.05; N, 16.20. Found: C,
78.62; H, 5.10; N, 16.27.
127.7, 127.8, 128.7, 139.0, 141.7, 162.3; IR (KBr) wCN
=
1626 cm−1; MS (m/z) calcd for C22H18N2: 310.1470.
Found: 310.1473; Anal. Calcd: C, 85.13; H, 5.85; N, 9.02.
Found: C, 85.11; H, 5.82; N, 9.00.
11. Compound 3f: mp>250°C; 1H NMR l (CDCl3) 3.05 (AB,
2H, J=16 Hz), 3.13 (AB, 2H, J=15.9 Hz), 6.98–7.42 (m,
8H), 7.92 (s, 1H), 9.51 (s, 1H), 10.01 (s, 1H); 13C NMR
l 29.9, 31.9, 45.9, 116.6, 117.7, 118.3, 119.4, 126.3, 127.5,
129.1, 129.5, 129.6, 131.9, 134.0, 164.6, 170.4; IR (KBr)
wNH=3191, 3315, 3442 cm−1, wCO=1685 cm−1; MS (m/z)
calcd for C17H15N3O: 277.1221. Found: 277.1215.
1
7. Compound 3b: mp 210°C; H NMR l (CDCl3) 3.30 (s,
4H), 3.90 (s, 6H), 6.94 (t, 2H, J=8 Hz), 7.20 (d, 2H, J=8
Hz), 7.70 (d, 2H, J=8 Hz), 10.70 (s, 1H); 13C NMR l
34.2, 36.7, 52.4, 117.7, 121.2, 122.8, 130.0, 131.7, 141.2,
150.7, 168.0; IR (KBr) wNH=3264 cm−1, wCN=2235 cm−1
,
wCO=1719 cm−1
375.1219. Found: 375.1204.
; MS (m/z) calcd for C21H17N3O4:
12. Compound 4a: mp>250°C; 1H NMR l (CDCl3) 3.04
(AB, 2H, J=15.9 Hz), 3.37 (AB, 2H, J=15.9Hz), 7.10 (d,
2H, J=8.5 Hz), 7.31 (t, 2H, J=8.5 Hz), 7.48 (t, 2H,
J=8.5 Hz), 7.64 (d, 2H, J=8.5 Hz), 8.45 (s, 2H), 9.30 (s,
2H); 13C NMR l 30.4, 46.5, 115.8, 117.9, 128.7, 128.9,
130.2, 134.0, 158.3; IR (KBr) wNH=3162 cm−1; MS (m/z)
calcd for C17H16N4O2: 308.1256. Found: 308.1273.
1
8. Compound 3c: mp>250°C; H NMR l (CDCl3) 3.30 (s,
4H), 4.00 (s, 6H), 7.45 (d, 2H, J=7.9 and 1.3 Hz), 7.86
(d, 2H, J=1.3 Hz), 8.00 (dd, 2H, J=7.9 Hz); 13C NMR
l 34.5, 36.1, 53.7, 119.7, 122.1, 124.6, 129.4, 131.4, 132.5,
154.6, 167.7; IR (KBr) wNH=3291 cm−1, wCN=2234 cm−1
,
wCO=1725 cm−1
375.1219. Found: 375.1204.
. MS (m/z) calcd for C21H17N3O4: