Vicarious nucleophilic amination of Nitroquinolines with 4-amino-1,2,4-triazole

Article abstract of DOI:10.1139/V08-051

3-, 5-. 6-, 7- and 8-Nitroquinolines react with 4-amino-l,2,4-triazole in basic medium (potassium tert-butoxide-dimethyl sulfoxide) giving amino products of the vicarious nucleophilic substitution (VNS) of hydrogen, predominantly at ortho position to the nitro group, except 8-nitroquinoline, which reacts at para position. Additionally, furazano[3,4-f]- and furazano[3,4-zh]quinoline were obtained in the case of 5- and 8- nitroquinoline, respectively. 2-Nitroquinoline was aminated to 2-quinolino(l,2,4-triazol-4-yl)amine in these conditions.

Full text of DOI:10.1139/V08-051

682
Vicarious nucleophilic amination of nitroquinolines
with 4-amino-1,2,4-triazole
Barbara Szpakiewicz and Maria Grzegoóek
Abstract: 3-, 5-, 6-, 7- and 8-Nitroquinolines react with 4-amino-1,2,4-triazole in basic medium (potassium tert-
butoxide-dimethyl sulfoxide) giving amino products of the vicarious nucleophilic substitution (VNS) of hydrogen, pre-
dominantly at ortho position to the nitro group, except 8-nitroquinoline, which reacts at para position. Additionally,
furazano[3,4-f]- and furazano[3,4-h]quinoline were obtained in the case of 5- and 8- nitroquinoline, respectively. 2-
Nitroquinoline was aminated to 2-quinolino(1,2,4-triazol-4-yl)amine in these conditions.
Key words: nitroquinolines, vicarious nucleophilic substitution (VNS), 4-amino-1,2,4-triazole.
Résumé : Les 3-, 5-, 6-, 7- et 8-nitroquinoléines réagissent avec le 4-amino-1,2,4-triazole en milieu basique (tert-buty-
late de potassium dans le diméthylsulfoxyde) pour conduire à la formation de produits aminés par le biais d’une substi-
tution nucléophile indirecte (SNI) d’hydrogène, principalement en position ortho du groupe nitro, excepté dans le cas
de la 8-nitroquinoléine avec laquelle la substitution se fait en position para. De plus, dans les cas de la 5- et de la 8-
nitroquinoléine, on a aussi obtenu respectivement la furazano[3,4-f] et la furazano[3,4-h]quinoléine.
Mots-clés : nitroquinoléines, substitution nucléophile indirecte (SNI), 4-amino-1,2,4-triazole.
[Traduit par la Rédaction] Szpakiewicz and Grzegoóek 685
Introduction
cent to the NO2 group was occupied by a halogen or a
methyl group (6).
Many derivatives of aminoquinolines exhibit a wide spec-
trum of pharmacological and biological activities. Moreover,
aminoquinolines are important intermediates in organic syn-
thesis. Some examples of synthesis of aminonitroquinolines
have already been described previously. They have been
synthesized by the classical method, which is nucleophilic
substitution SNAr of halogen by amines in halogenonitro-
quinolines (1–3). Another way to obtain compounds men-
tioned above is dehydroamination of nitroquinolines. It has
been carried out as oxidative nucleophilic substitution of hy-
drogen (ONSH) (4–6) or vicarious nucleophilic substitution
(VNS) of hydrogen (7–10). Thus, Woïniak et al. described
that mono- and dinitroquinolines undergo selective amina-
tion, in liquid ammonia and potassium permanganate at
–33 °C, in the ortho position, relative to the nitro group,
with moderate to low yields, except 8-nitro- and 2-
nitroquinoline (found as unreactive) (4, 5). Additionally,
they studied the amination of halogeno and methyl deriva-
tives of nitroquinolines containing the substituents in the
benzene ring. The reported amination also undergoes giving
selectively ortho substituted products, relative to the nitro
group. No amination was observed when the position adja-
Huisgen (7) and Hasegawa et al. (8, 9) described the di-
rect amination of mononitroquinolines with hydroxylamine
in basic media, which leads to aminonitroquinolines. Mkosza
suggested that these reactions can be considered as examples
of the VNS reaction (10). In these reactions, Hasegawa ob-
tained furazanoquinolines in addition to the known amino
derivatives. He obtained furazano[3,4-f ]quinoline from 5-
nitro- and 6-nitroquinoline and furazano[3,4-h]quinoline
from 7-nitro- and 8-nitroquinoline (7, 8).
For the VNS amination of 5-nitro- and 6-nitroquinoline,
Mkosza and Bia»ecki used sulfenamides. In the first case,
they obtained the mixture of 6-amino- and 8-amino-5-
nitroquinoline and 6-amino-5-nitrosoquinoline with 90%–
98% yield, and in the second case, they obtained only
5-amino-6-nitroquinoline (98% yield) (10).
A variety of regents for the direct amination of nitroarenes
and nitrosubstituted heteroaromatic compounds in VNS re-
actions were described in literature. These are 4-amino-
1,2,4-triazole (11–15), O-alkylhydroxylamines (16), 1,1,1-
trimethylhydrazinium iodide (17–20), and hydroxylamine
(7–9) and sulfenamides (10, 21) mentioned above.
In this paper, we report the results of our studies on the
amination of nitroquinolines 1 via the vicarious nucleophilic
substitution (VNS) of hydrogen with 4-amino-1,2,4-triazole.
This is the continuation of our research on the synthesis of
amino nitroaromatic compounds (2, 22).
Received 20 December 2007. Accepted 28 February 2008.
Published on the NRC Research Press Web site at
canjchem.nrc.ca on 17 May 2008.
B. Szpakiewicz1 and M. Grzegoóek. Institute of Organic
Chemistry and Technology, Cracow University of
Results and discussion
Technology, ul. Warszawska 24, PL-31155 Kraków, Poland.
The amination of the nitroquinolines 1a–1e with 4-amino-
1,2,4-triazole was carried out in the presence of potassium
tert-butoxide-DMSO solution at room temperature. The
1Corresponding author (e-mail:
bszpak@indy.chemia.pk.edu.pl).
Can. J. Chem. 86: 682–685 (2008)
doi:10.1139/V08-051
© 2008 NRC Canada

Szpakiewicz and Grzegoóek
683
Scheme 1.
Scheme 2.
structures of these products were determined on the basis of
1
their physical properties (mp, spectral data: H NMR, IR,
and MS) and comparison with data from literature or with
reference samples in some cases. The results of amination
are compiled in Scheme 1.
The reaction of nitroquinolines 1a–1e with 4-amino-1,2,4-
triazole proceeds in accordance with vicarious SNArH mech-
anism, described by Mkosza (23), which we present as an
example of amination of 5-nitroquinoline (1b) (Scheme 2).
The reaction occurs between 5-nitroquinoline (1b) and the
anion generated from 4-amino-1,2,4-triazole, in presence of
a strong base (potassium tert-butoxide). In the first step, ad-
dition of the anion to the 5-nitroquinoline (1b) results in for-
mation of σ adducts, type of Meisenheimer complexes, in
ortho and para positions relative to the nitro group. Immedi-
ate formation of an intense dark-red colour was observed.
The σ adducts undergo base-induced β-elimination of 1,2,4-
triazole to form carbanions, which are protonated during the
work up procedure, giving 6-amino-5-nitro- (2b) and 8-
amino-5-nitroquinoline (2b′). Amination of 3- (1a), 6- (1c)
and 7-nitroquinoline (1d) occurs regioselectively giving
products of substitution at ortho position to the nitro group:
4-amino-3-nitro- (2a), 5-amino-6-nitro- (2c), 8-amino-7-
nitroquinoline (2d) with moderate to high 52%, 98%, and 84
% yields, respectively.
Scheme 3.
Scheme 4.
1,2,4-triazole that, by intramolecular cyclization, forms
Amination of 5-nitro- (1b) and 8-nitroquinoline (1e) with
4-amino-1,2,4-triazole in DMSO in the presence of t-BuOK
at room temperature afforded furazanoquinolines beside the
corresponding substituted aminonitroquinolines. In the case
of 1b, we obtained the products of ortho and para substitu-
tion of hydrogen: 6-amino-5-nitro- (2b) and 8-amino-5-
nitroquinoline (2b′), as given above, together with
furazano[3,4-f ]quinoline (3) with 15%, 19%, and 35%
yields, respectively (Scheme 1). On the other hand, 8-
nitroquinoline (1e) gave 5-amino-8-nitroquinoline (2e)
(47%) and furazano[3,4-h]quinoline (4) (23%) under the
same conditions.
To explain the formation of furazanoquinolines 3 and 4,
we propose the mechanism for synthesis of furazano[3,4-
f ]quinoline (3) from 5-nitroquinoline (1b) in Scheme 3.
This mechanism is in accordance with the one suggested by
Hasegawa for similar reaction (8).
furazano[3,4-f ]quinoline (3).
In the case of 8-nitroquinoline (1e), the reaction progress,
monitored by thin layer chromatography, indicates the
formation of furazano[3,4-h]quinoline (4) after 5 min of the
reaction time. The quick formation of furazane proves that
σ adduct undergoes intramolecular transformation more
readily than β-elimination of 1,2,4-triazole. This confirms
the presented mechanism of reaction and explains why we
did not obtain ortho amino isomer instead of only para iso-
mer, as a product of amination.
2-Nitroquinoline (1f), in contrast to other studied
nitroquinolines 1a–1e, does not undergo vicarious amination
by 4-amino-1,2,4-triazole but only displacement of the 2-
nitro group occurs, giving 2-quinolino(1,2,4-triazol-4-
yl)amine (2f) (Scheme 4).
Apparently, the nucleophilic displacement of the highly
labile nitro group at C-2 position of the pyridine ring in 1f,
takes place more easily than the vicarious nucleophilic sub-
stitution of hydrogen by amino group at another carbon
atom. A similar behaviour of 2-nitroquinoline was observed
for oxidative methylamination reaction (2).
In the first step, addition of 4-amino-1,2,4-triazole anion
at the ortho position to the nitro group gives the σ adduct, in
which the ortho ring hydrogen undergoes shifting to the oxy-
gen of the nitro group. Subsequently, elimination of
hydroxyl group leads to 4-(5-nitroso-6-quinolylamino)-
© 2008 NRC Canada

684
Can. J. Chem. Vol. 86, 2008
precipitate and was worked up in the manner described be-
low.
Summary
In conclusion, we have presented the direct amination of
3-, 5-, 6-, 7- and 8-nitroquinolines (1a–1e) with 4-amino-
1,2,4-triazole under the VNS reaction conditions. Using the
4-amino-1,2,4-triazole permits to obtain aminonitroquino-
lines in a short time, with moderate to high yields, substi-
tuted mainly in ortho position to the nitro group. 5-
Nitroquinoline (1b) gave, besides the ortho amino product,
the para isomer, and in the case of 8-nitroquinoline (1e),
only the para amino product was obtained. In both cases, as
Amination of 3-nitroquinoline (1a)
4-Amino-3-nitroquinoline (2a): orange precipitate 98 mg
(52%) with mp 258–260 °C (subl.) (without purification,
chromatographically pure) and after recrystallization from
EtOH: yellow needles with mp 265–266 °C (lit. (1) 261 °C;
(4) 274–275 °C; (2) 270–272 °C). IR (νmax) (cm–1): 3385,
1
3304, 3175 (NH), 1537 (NO2, as), 1337 (NO2, s). H NMR
(DMSO-d6) δ: 9.18 (s, 2-H), 9.01 (br s, NH2), 8.58 (dd, 5-H
the products of transformation of ortho
furazano[3,4-f ]- (3) and furazano[3,4-h]quinoline (4) were
also obtained.
σ
adducts,
or 8-H), 7.96–7.51 (m, 6-H, 7-H and 5-H or 8-H), J6,7
4.40, J5,6 = J7,8 = 8.56, J5,7 = J6,8 = 1.24 Hz.
=
2-Nitroquinoline (1f) reacted with replacement of the ni-
tro group, giving 2-quinolino(1,2,4-triazol-4-yl)amine (2f).
Amination of 5-nitroquinoline (1b)
The yellow residue was separated on the chromatographic
column using chloroform as eluent. The first fraction gave
60 mg (35%) of furazano[3,4-f]quinoline (3) colourless nee-
Experimental
1
dles, mp 132–134 °C (lit.(8) 138–139 °C; (26) 134 °C). H
NMR (CDCl3) δ: 9.03 (dd, 2-H), 8.85 (dd, 4-H), 7.91 (s, 7-
Melting points (uncorrected) were determined on a
Boetius melting point apparatus. The H NMR spectra were
1
H, 8-H), 7.63 (dd, 3-H), J2,3 = 4.60, J2,4 = 1.68, J3,4
=
8.80 Hz. MS m/z (%): 171 [M+] (100), 141 [M+ – NO].
recorded on Tesla BS-587A (80 MHz) spectrometers using
TMS as internal standard. Chemical shifts are expressed in
parts per million (ppm). The infrared spectra were recorded
on Bio-Rad FTS-175C spectrometer (in potassium bromide
pellets). Mass spectra (EI) were recorded with a Varian-
MAT 112 spectrometer at 70 eV. Elemental analysis was
performed on a PerkinElmer 2400 analyser. The reaction
products were analysed by thin-layer chromatography (TLC)
on silica gel or aluminium oxide plates (Merck 60F254). The
progress of reactions was monitored by TLC on silica gel
using dichloromethane as eluent. Aluminium oxide type 507
C was used for column chromatography.
The second fraction, after removing of the eluent by evap-
oration, gave 36 mg (19%) of 8-amino-5-nitroquinoline (2b′)
as orange needles with mp 201–202 °C (lit. (8) 197–198 °C;
(2) 194–195 °C). IR (νmax) (cm–1): 3402, 3308, 3212 (NH),
1
1524 (NO2, as), 1392 (NO2, s). H NMR (CDCl3) δ: 9.40
(dd, 4-H), 8.79 (dd, 2-H), 8.52(d, 6-H), 7.64 (dd, 3-H), 6.79
(d, 7-H), 5.97 (br s, NH2), J2,3 = 4.16, J2,4 = 1.56, J3,4
=
8.80, J6,7 = 8.92 Hz. The compound 2b′ showed properties
identical to the reference sample obtained independently (22).
From the third fraction was isolated 28 mg (15%) 6-
amino-5-nitroquinoline (2b) as yellow needles, after
recrystallization from toluene, mp 176–178 °C (lit. (10)
173–175 °C, (5) 176–178 °C). IR (νmax) (cm–1): 3437, 3412,
3295, (NH), 1511 (NO2, as), 1300 (NO2, s). 1H NMR
(CDCl3) δ: 9.12 (dd, 4-H), 8.72 (dd, 2-H), 8.05 (d, 8-H),
7.54 (dd, 3-H), 7.16 (d, 7-H), 6.69 (br s, NH2), J2,3 = 4.20,
J2,4 = 1.60, J3,4 = 8.80, J7,8 = 9.28 Hz.
Synthesis of starting and reference compounds
3-Nitro-(1a (24)), 2-nitro-(1f (5)) were prepared according
to the literature procedures. 5-(1b), 6-(1c), 7-(1d), and 8-
Nitroquinoline (1e) were obtained by Skraup reaction from
the respective aminonitrobenzenes (25). Other reagents, 4-
amino-1,2,4-triazole, t-BuOK, and DMSO were commercial
products from Merck and Aldrich and were dried before use,
except t-BuOK.
Amination of 6-nitroquinoline (1c)
5-Amino-6-nitroquinoline (2c): yellow solid 185 mg
(98%) with mp 283–284 °C (without purification,
chromatographically pure) and after recrystallization from
toluene: yellow needles, mp 285–286 °C subl. (lit. (7) 283–
284.5 °C; (5) 287–288 °C subl.). IR (νmax) (cm–1): 3404,
Amination of nitroquinolines 1a–1f with 4-amino-1,2,4-
triazole
1
3295, 3168 (NH), 1584 (NO2, as), 1324 (NO2, s). H NMR
General procedure
(DMSO-d6) δ: 9.10–8.90 (m, 2-H, 4-H), 8.74 (br s, NH2),
8.22 (d, 7-H), 7.61 (dd, 3-H), 7.15 (d, 8-H), J2,3 = 4.40,
J3,4 = 8.00, J7,8 = 9.64 Hz.
The mixture of the respective nitroquinolines 1a–1f
(174 mg, 1 mmol) and 4-amino-1,2,4-triazole (100–126 mg,
1.2–1.5 mmol) in dimethyl sulfoxide (3–5 mL) was added at
room temperature to a stirred suspension of t-BuOK
(280 mg, 2.5 mmol) in dimethyl sulfoxide (2 mL), except
1e, where 522 mg (3 mmol) of 1e and respective amount of
remaining reagents were used. The reaction mixture was
stirred vigorously for 0.25–0.7 h, and 4 h in the case of
2-nitroquinoline (1f), at room temperature. The resulting
red-brown solution was poured into saturated NH4Cl, the
precipitate was filtered off, washed with water, and dried.
The filtrate was periodically extracted with dichloromethane
or chloroform (3 × 25 mL) in some cases. After evaporation
of the solvent, the residue was combined with the obtained
Amination of 7-nitroquinoline (1d)
8-Amino-7-nitroquinoline (3d): orange crystals 159 mg
(84%) with mp 189–190 °C (without purification, chromato-
graphically pure) (lit. (5) 188–189 °C; (1) 185–185.5 °C).
The compound showed properties identical (mp, IR spec-
trum, and coefficient Rf (TLC)) with those of the reference
samples. IR (νm1ax) (cm–1): 3477, 3359 (NH), 1523 (NO2, as),
1321 (NO2, s). H NMR (DMSO-d6) δ: 8.91 (dd, 2-H), 8.43
(s, NH2), 8.34 (dd, 4-H), 8.04 (d, 6-H), 7.76 (dd, 3-H), 7.93
(d, 5-H), J2,3 = 4.16, J3,4 = 8.16, J2,4 = 1.76, J5,6 = 9.36 Hz.
© 2008 NRC Canada

Szpakiewicz and Grzegoóek
685
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The yellow residue was dissolved in 50 mL of dichloro-
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8-nitroquinoline (2e) with mp 250–251 °C (without purifica-
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1298 (NO2, s). H NMR (DMSO-d6) δ: 8.97 (dd, 2-H), 8.70
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6.67 (d, 6-H), J2,3 = 4.12, J3,4 = 8.68, J2,4 = 1.52, J6,7
8.8 Hz.
=
The filtrate, after condensation, was separated on the
chromatographic column using dichloromethane as eluent.
The first fraction gave 120 mg (23%) of furazano[3,4-
h]quinoline (4), colourless plates, mp 176–177 °C (lit. (8)
1
177.5–178 °C). H NMR (CDCl3) δ: 9.04 (dd, 2-H), 8.17
(dd, 4-H), 7.84–7.58 (m, 3-H, 5-H, 6-H), J2,3 = 4.56, J2,4
=
1.62, J3,4 = 8.08 Hz. MS m/z (%): 171 [M+] (100), 141
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The second fraction, after removing of the eluent by evap-
oration, afforded additional 36 mg compound, which showed
the same properties, mp and coefficient Rf, as 5-amino-8-
nitroquinoline (2e). Total yield of 2e is 47%.
61, 2934 (1996).
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(2004).
Amination of 2-nitroquinoline (1f)
2-Quinolino(1,2,4-triazol-4-yl)amine (2f): colourless crys-
tals, 171 mg (81%), after recrystallization from methanol,
mp 258–259 °C. IR (νmax) (cm–1): 3437 (NH), 1650 (δ NH
1
(s)). H NMR (CD3OD) δ: 8.67 (s, 2H-triazole), 8.11 (d,
4-H), 7.79–7.28 (m, 5–8-H, NH), 6.85 (d, 3-H), J3,4
=
8.72 Hz. MS m/z (%): 211 [M+] (19), 129 (100). Anal. calcd.
for C11H9N5 (211.23): C 62.55, H 4.29, N 33.16; found: C
62.20, H 4.17, N 32.76.
Acknowledgements
Autors wish to thank Dr. E.Cholewka for measuring the
1H NMR and IR spectra.
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© 2008 NRC Canada