Vicarious nucleophilic amination of nitroquinolines by 1,1,1- trimethylhydrazinium iodide

Article abstract of DOI:10.1002/jhet.5570450652

(Chemical Equation Presented) The amination of 3-, 5-, 6-, 7- and 8-nitroquinoline via the vicarious nucleophilic substitution of hydrogen (VNS) with 1,1,1-trimethylhydrazinium iodide (TMHI) in the presence of t-BuOK in DMSO was studied. The amination occurs regioselectively giving ortho or ortho and para isomers relative to the nitro group with a high yield (95-86%). 2-Nitroquinoline does not undergo vicarious amination but displacement of the labile nitro group by an amino group occurs and then transformation to an imine compound and hydrolysis gives 2(1H)-quinolinone.

Full text of DOI:10.1002/jhet.5570450652

Nov-Dec 2008
1879
Vicarious Nucleophilic Amination of Nitroquinolines
by 1,1,1-Trimethylhydrazinium Iodide
Maria Grzego ek*
Institute of Organic Chemistry and Technology, Cracow University of Technology, ul. Warszawska 24, PL-
31155 Kraków, Poland
Received February 25, 2008
NH2
TMHI
O2N
O2N
t-BuOK/DMSO
N
N
1
2
1a: 3-NO2
1b: 5-NO2
1c: 6-NO2
1d: 7-NO2
1e: 8-NO2
2a: 4-NH2
2b: 6-NH2 ; 2b`: 8-NH2
2c: 5-NH2
2d: 8-NH2
2e: 7-NH2 ; 2e`: 5-NH2
The amination of 3-, 5-, 6-, 7- and 8-nitroquinoline via the vicarious nucleophilic substitution of
hydrogen (VNS) with 1,1,1-trimethylhydrazinium iodide (TMHI) in the presence of t-BuOK in DMSO was
studied. The amination occurs regioselectively giving ortho or ortho and para isomers relative to the nitro
group with a high yield (95-86%). 2-Nitroquinoline does not undergo vicarious amination but
displacement of the labile nitro group by an amino group occurs and then transformation to an imine
compound and hydrolysis gives 2(1H)-quinolinone.
J. Heterocyclic Chem., 45, 1879 (2008).
INTRODUCTION
are comparatively simple. Many derivatives of amino-
quinolines exhibit a wide spectrum of pharmacological
and biological activities. They also establish important
intermediates in organic synthesis.
Vicarious nucleophilic substitution (VNS) of hydrogen
[1,2] is now a well-established general method for the
introduction of a variety of substituents into electrophilic
arenes, particularly those containing nitro groups.
Besides, widely examined carbanions, the introduction of
oxygen, nitrogen, sulphur and halogen substituents are
also possible.
This paper reports the results of the vicarious
nucleophilic amination of x-mononitroquinolines (x = 2-
8) by 1,1,1-trimethylhydrazinium iodide (TMHI).
The literature quoted below describes some examples
of synthesis of aminonitroquinolines. At first they were
obtained from halogenonitroquinolines by the classical
method of nucleophilic substitution SNAr of halogen, with
amines [14-16] and then, by the dehydroamination of
nitroquinolines. These reactions can proceed by
nucleophilic replacement of aromatic hydrogen, SNH
substitution, by oxidative (ONSH) or vicarious amination
(VNS). Woꢀniak et al., aminated x-mononitroquinolines
(x = 2-8) [15,17] in a solution of potassium permanganate
in liquid ammonia -33 °C. The oxidative amination occurs
very selectively giving only ortho substitution relative to
the nitro group, aminonitroquinolines with moderate to
low yields [15,17], except 2-nitro- and 8-nitroquinoline,
which was found to be unreactive [15]. Hasegawa et al.,
[3] reported the amination of 5-nitro-, 6-nitro-, 7-nitro-
and 8-nitroquinoline using hydroxylamine in potassium
hydroxide as an aminating agent, obtaining a novel
product, furazanoquinoline, besides the known amino
derivatives substituted in ortho and/or para positions to
the nitro group [3]. Mꢁkosza and Biaꢂecki [11] used
sulfenamides as aminating agents. With 5-nitroquinoline
obtained a mixture of 6-amino-5-nitro- (52%), 8-amino-5-
The direct amination by VNS methodology requires
suitable amine nucleophiles, which contain a good leaving
group at the nucleophilic centre. These effective
amination reagents are hydroxylamine [3], 1,1,1-
trimethylhydrazinium iodide (TMHI) [4-6], 4-amino-[7,8]
or 4-alkylamino-1,2,4-triazoles [9] and sulfenamides
[10,11].
Application of the vicarious nucleophilic amination
seems to be of special interest in considering high
regioselectively and good yields for this type of reaction.
The products of VNS amination, particularly those with
amino substituents in the ortho position to the nitro group,
can serve as convenient and versatile starting material for
the synthesis of heterocyclic compounds.
The efficacy of TMHI as a VNS aminating reagent was
tested by reacting them with a variety of nitroarenes
[4,6,12,13] and nitroazoles [13] giving excellent yields.
These results induced studing the possibility of using the
1,1,1-trimethylhydrazinium iodide as a VNS reagent for
the amination of nitroquinolines. Additionally, the
vicarious nucleophilic amination appeared to be of special
interest with regard to the conditions of reactions, which

1880
M. Grzegoꢀek
Vol 45
8-amino-7-nitroquinoline (2d) respectively with high
yields (Scheme 1).
nitro- (17%) and 6-amino-5-nitrosoquinoline (29%) and
with 6-nitroquinoline, 5-amino-6-nitroquinoline (98%)
[11].
Scheme 1
RESULTS AND DISCUSSION
The amination of the mononitroquinolines 1a-f by
1,1,1-trimethylhydrazinium iodide was carried out in
base-solvent system: potassium tert-butoxide-dimethyl
sulfoxide at room temperature. The results of reactions are
compiled in Scheme 1. The structure of the obtained
amino products (known compounds), has been established
1a: 3-NO2
1b: 5-NO2
2a: 3-NO2, 4-NH2 (92%)
2b: 5-NO2, 6-NH2 (61%)
2b`:5-NO2, 8-NH2 (26%)
2c: 6-NO2, 5-NH2 (95%)
2d: 7-NO2, 8-NH2 (92%)
2e: 8-NO2, 7-NH2 (68%)
2e`:8-NO2, 5-NH2 (18%)
1
on the basis of spectroscopic data, in particular H NMR
1c: 6-NO2
1d: 7-NO2
1e: 8-NO2
and IR and also by comparing their properties with the
data given in the literature or with independently
synthesised reference samples.
Amination of 3-nitroquinoline (1a) with 1,1,1-tri-
methylhydrazinium iodide affords 4-amino-3-nitro-
quinoline (2a) with high yield. This determined
unequivocally the position of the amino group in 2a (2 or
4) carried out by comparison of its properties (RF, mp and
1H NMR and IR spectrum) with reference to the sample
obtained by oxidative amination[17] (Scheme 1).
The results of amination of nitroquinolines 1a-e with
1,1,1-trimethylhydrazinium iodide (TMHI) confirm that
the amination proceeds in accordance with the vicarious
SNArH mechanism given by Mꢁkosza [1,2]. The course of
reaction was presented with the example of reaction 5-
nitroquinoline (1b) with TMHI (Scheme 2).
Amination of 5-nitroquinoline (1b) with TMHI gives a
mixture of 6-amino- (2b) and 8-amino-5-nitroquinoline
(2b') with a ratio of 2b:2b' = 70:30 likewise as 8-
nitroquinoline (1e), gave 7-amino- (2e) and 5-amino-8-
nitroquinoline (3e') with a ratio of 79:21 respectively. The
ratio of ortho/para isomers was determined on the basis
of chromatographic separation (Scheme 1).
Generally, the reaction process takes place between
nitroquinolines 1a-e and the ylide generated from 1,1,1-
trimethylhydrazinium iodide (Scheme 2). In the presence
of a strong base (t-BuOK), deprotonation of TMHI
occurs, giving trimethylammonium imide (TMAI). In the
first step, addition of the ylide TMAI to the
nitroquinolines 1a-e results in formation of ꢀ adducts in
the ortho or ortho and para position relative to the nitro
group. The ꢀ adducts undergo base-induced deprotonation
Treatment of 6-nitro- (1c), and 7-nitroquinoline (1d)
with TMHI give 5-amino-6-nitroquinoline (2c) and
Scheme 2

Nov-Dec 2008
Vicarious Nucleophilic Amination of Nitroquinolines by 1,1,1-Trimethylhydrazinium Iodide
1881
chloroform as eluent. Preparative chromatography was
performed on a column packed with Aluminum oxide type 507
C (Fluka). The ratio of ortho/para isomers 2b/2b' and 2e/2e'
was established by preparative chromatography.
Starting materials and Reagents. 3-Nitro-(1a) [18] and 2-
nitroquinolines (1f)[15] were obtained according to literature
procedures. 5- (1b), 6- (1c), 7- (1d) and 8-Nitroquinolines (1e)
[19] were prepared by Skraup reaction from the respective
aminonitrobenzenes. Other reagents, 1,1,1-trimethylhydrazinium
iodide (TMHI), t-BuOK, DMSO were commercial product from
Aldrich.
General Procedure for Amination of Mononitroquinolines
1a-f. To a solution of 0.35 g (2 mmol, 1 equiv.) of the
respective mononitroquinolines 1a-f and 0.61g (3 mmol, 1.5
equiv.) TMHI in anhydrous DMSO (10-15 mL) was added the
solid of t-BuOK (0.67 g, 6 mmol, 3 equiv.). The reaction
mixture was stirred at room temperature until the starting
material was completely reacted, as indicated by TLC
monitoring (1-8 h). The resulting dark-red solution was poured
into saturated aqueous NH4Cl. The obtained precipitate was
collected by filtration, washed with water, dried and purified
by recrystallization. Additionally, in the case of reactions 1b,
with simultaneous elimination of trimethylamine to form
carbanions which are protonated during the work up
procedure, giving products 2a-e.
The substantial predominance of the ortho isomers in
the case of amination of 1b and 1e is presumably
connected with the stability of the ꢀ adduct. The addition
of the nucleophile to the ortho position relative to the NO2
group will give a more stable adduct than in the para
position. In contrast to other studied nitroquinolines 1a-e,
2-nitroquinoline (1f) does not undergo vicarious
amination by treatment with THMI, giving 2(1H)-
quinolinone (2f). The nucleophilic displacement of the
highly labile nitro group at the C-2 position by
trimethylamonium imide (TMAI) take place more easily
than the vicarious substitution of hydrogen at an adjacent
carbon atom to the nitro group. A possible mechanistic
pattern for the substitution of the nitro group is presented
in Scheme 3.
Scheme 3
1e and 1f, the filtrate was periodically extracted with
chloroform (3 x 30 mL). The combined chloroform phases
were washed with water (30 mL) and dried (MgSO4). After
evaporation of the solvent, the residue was combined with the
obtained precipitate and was separated by column
chromatography or recrystallized.
The substitution of the nitro group occurs by the
addition of the trimethylammonium imide anion (TMHI)
followed by the departure of NO2 anion. The reaction
-
proceeds via an anionic ꢀ adduct that can be formed by
analogy to the ꢀH adduct. The transformation of the
substituted amino group to imine and then its hydrolysis,
gives 2(1H)-quinolinone (1f).
In conclusion, the THMI reagent is effective for direct
amination of nitroquinolines in VNS reactions. These
reactions proceed selectively under mild conditions and
can be synthetically useful with regard to excellent yields
(95-86%) and high pure obtained amino products.
Amination of 3-nitroquinoline (1a). The yellow precipitate
was isolated after 4 h and recrystallized from ethanol to give
0.35 g (92%) of 4-amino-3-nitroquinoline (2a), yellow needles
with mp 276-277 °C (lit. [14] 261 °C, lit.[17] 274-275 °C, lit.
[18] 270-272 °C); ir (potassium bromide): 3385, 3304, 3175
(NH), 1537 (NO2, as), 1337 (NO2, s) cm-1; 1H nmr (DMSO-d6): ꢁ
9.18 (s, 1H, 2-H), 9.01 (broad s, 2H, NH), 8.58 (dd, 1H, 5-H or
8-H, J5,6 = 8.56, J5,7 = 2.4 Hz), 7.96-7.51 (m, 3H, 6-H, 7-H, J6,7
4.40, J7,8 = 8.56 Hz and 5-H or 8-H, J6,8 = 2.4 Hz).
=
EXPERIMENTAL
Amination of 5-nitroquinoline (1b). The amination of 1b
was carried out for 8 h according to the general procedure. The
yellow residue was dissolved in chloroform and separated by
column chromatography using the same solvent as the eluent.
Melting points (uncorrected) were determined on a Boetius
apparatus. The H NMR spectra were recorded on Tesla BS-
1
The first fraction afforded 0.10
g (26%) of 8-amino-5-
587A (80 MHz) spectrometers using TMS as an internal
standard; the chemical shifts are given in ppm (ꢁ); and coupling
constants are taken from the expanded spectra. The infrared
spectra were recorded on Bio-Rad FTS-175C spectrophotometer
(in potassium bromide pellets). The progress of reactions was
monitored by thin-layer chromatography (TLC) on aluminum
foil plates with aluminum oxide 60F 254 (Merck) using
nitroquinoline (2b'), orange needles with mp 195-197 °C (lit.
[11] 195-197 °C, lit. [14,18] 194-195 °C); ir (potassium
bromide): 3404, 3310, 3213 (NH), 1524 (NO2, as). 1392 (NO2,
s) cm-1 ; 1H nmr (DMSO-d6): ꢁ 9.28 (dd, 4-H ), 8.84 (dd, 2-H, J2,3
= 4.16, J2,4 = 1.68 Hz), 8.48 (d, 6-H), 7.80 (dd, 3-H, J3,4 = 8.96
Hz), 6.85 (d, 7-H).

1882
M. Grzegoꢀek
Vol 45
The second fraction, after removing of the eluent by
residue combined with precipitate and crystallized from
methanol, yielding 0.18 g (62%) of creme crystals of 2(1H)-
quinolinone (2f) mp 198-200 °C (lit. [22] 199-200 °C); ir
(potassium bromide): 3255 (NH), 3126 - 2848 (OH), 1651(CO)
evaporation, gave 0.23 g (61%) of 6-amino-5-nitroquinoline
(2b), yellow needles with mp 176-178 °C (lit. [15,18] 176-178 °C);
ir (potassium bromide): 3432, 3412, 3295 (NH), 1511 (NO2, as),
1
1375 (NO2, s) cm-1; H nmr (DMSO-d6): ꢀ 8.90 (dd, 4-H), 8.63
1
cm-1 ; H nmr (DMSO-d6): ꢀ 11.73 (broad s, 1H, OH), 7.91, (d,
(dd, 2-H, J2, 3 = 4.40, J2, 4 = 1.44 Hz), 8.23 (broad s, 2H, NH),
4-H), 7.66 (d, 8-H or 5-H), 7.48, (dd, 7-H or 6-H), 7.29 (d, 5-H
or 8-H, J5, 6 = 7,6 Hz), 7.12 (dd, 6-H or 7H, J6,7 = 6.72, J7, 8 = 7.6
Hz), 6.51 (d, 3-H, J3, 4 = 9.52 Hz).
7.94 (d, 8-H), 7.58 (dd, 3-H, J3, 4 = 8.80 Hz), 7.42 (d, 7-H, J7, 8
9.52 Hz).
=
Amination of 6-nitroquinoline (1c). 5-Amino-6-nitro-
quinoline (2c) obtained after 1 h as yellow needles, yield 0.36 g
(95%) with mp 285-287 °C (without purification, chromato-
graphically pure) (lit. [15] 287-288 °C); ir (potassium bromide):
3404, 3295, 3168 (NH), 1584 (NO2, as), 1324 (NO2, s) cm-1 ; 1H
nmr (DMSO-d6): ꢀ 9.10-8.90 (m, 2H, 2-H, 4-H, J2, 3 = 4.40 Hz ),
8.74 (broad s, 2H, NH), 8.22 (d, 7-H, J7, 8 = 9.64 Hz), 7.60 (dd,
3-H, J3, 4 = 8.00 Hz), 7.15 (d, 8-H).
Acknowledgements. I am thankful to Dr. Cholewka for
measuring the 1H NMR and IR spectra.
REFERENCES
*
Author to whom correspondence
should be addressed;
Telephone/Fax: 048-12-628-20-37; E-mail: magre@indy.chemia.
pk.edu.pl
Amination of 7-nitroquinoline (1d). 8-Amino-7-nitro-
quinoline (2d) obtained after 2 h as orange needles, yield 0.35 g
(92%) with mp 188-189 °C (without purification, chromato-
graphically pure) (lit.[14] 185-185.5 °C, lit.[15] 188-189 °C).
The compound showed properties identical (mp, ir spectrum)
with reference sample. Ir (potassium bromide): 3477, 3359
[1] Mꢁkosza, M.; Wojciechowski, K. Liebigs Ann/Recueil 1997,
1805.
[2] Mꢁkosza, M. Synthesis 1991, 103.
[3] Hasegawa, M.; Takabatake, T.; Miyazawa, T. Yakugaku
Zasshi 2001, 121, 379; Chem. Abstr. 2001, 135, 180713x.
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[5] Schmidt, R.D.; Lee, G.S.; Pagoria, P.F.; Mitchell,
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Gilardi, R. J. Org. Chem. 2003, 68, 2498.
1
(NH), 1523 (NO2, as), 1321 (NO2, s) cm-1 ; H nmr (DMSO-d6):
ꢀ 8.91 (dd, 2-H, J2,3 = 4.16, J2,4 = 1.76 Hz) , 8.43 (broad s, 2H,
NH), 8.34 (dd, 4-H), 8.04 (d, 6-H), 7.76 (dd, 3-H, J3,4 = 8.16
Hz), 7.93 (d, 5-H, J5,6 = 9.36 Hz).
[7] Katritzky, A.R.; Laurenzo, K.S.; Schmidt, R.D. J. Org.
Chem. 1986, 51, 5039.
[8] Mꢁkosza, M.; Podraza, R. Eur. J. Org. Chem. 2000, 193.
[9] Katritzky, A.R.; Laurenzo, K.S. J. Org. Chem. 1988, 53,
3978.
[10] Mꢁkosza, M.; Biaꢂecki, M. J. Org. Chem. 1992, 57, 4784.
[11] Mꢁkosza, M.; Biaꢂecki, M. J. Org. Chem. 1998. 63, 4878.
[12] Krylova, O.V.; Elokhina, V.N.; Nakhmanovich, A.S.; Larina,
L.I.; Lopyrev, V.A Russ. J. Org. Chem. 2001, 37, 887.
[13] Titova, I.A.; Vakul 'skaya, T.I.; Larina, L.I.; Mizandrontsev,
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[14] Collona, M.; Montanari, I. Gazz. Chim. Ital. 1951, 81, 744.
[15] Woꢃniak, M.; Bara ski, A.; Nowak, K.; Van der Plas, H.C. J.
Org. Chem. 1987, 52, 5643.
Amination of 8-nitroquinoline (1e). The amination of 1e
was carried out for 4 h according to the general procedure. The
yellow residue (0.37 g) separated by the column chromato-
graphy using the mixture of chloroform and ethyl acetate (1:1)
as eluent. The first fraction gave 0.26 g (68%) of 7-amino-8-
nitroquinoline (3e), orange needles with mp 203- 205 °C (lit.
[20] 203-204.5 °C); ir (potassium bromide): 3433, 3313, 3185
(NH), 1507 (NO2, as), 1284 (NO2, s) cm-1; 1H nmr (DMSO-d6): ꢀ
8.74 (dd, 2-H, J2, 3 = 4.4, J2, 4 = 1.68 Hz), 8.20 (dd, 4-H), 7.84 (d,
5-H, J5, 6 = 8.08 Hz), 7.32 (dd, 3-H, J3, 4 = 8.16 Hz), 7.21 (d, 6-
H), 6.87 (broad s, 2H, NH).
The second fraction, after removing of the eluent, afforded
0.07 g (18%) of 5-amino-8-nitroquinoline (2e '), orange needles
with mp 253-255 °C (lit. [21] 252-253 °C); ir (potassium
bromide): 3456, 3438, 3324, 3204 (NH), 1576 (NO2, as), 1298
[16] Gerster, J.F. U.S.Patent 4689338, 1987; Chem. Abstr. 1988,
108, 75403r.
[17] Tondys, H.;.Van der Plas, H.C.; Woꢃniak, M. J. Heterocycl.
Chem. 1985, 22, 353.
1
(NO2, s) cm-1; H nmr (DMSO-d6): ꢀ 8.97 (dd, 2-H, J2, 3 = 4.12,
J2, 4 = 1.52 Hz), 8.70 (dd, 4-H), 8.19 (d, 7-H), 7.54 (dd, 3-H, J3, 4
[18] Albert, A.; Brown, D.J.; Duewell, H. J. Chem. Soc. 1948,
1284 ; Clemo, G.R.; Swan, G.A. J. Chem. Soc. 1945, 867.
[19] Filippi, J. Bull. Soc. Chim. Fr. 1968, 259.
[20] Hasegawa, M.; Okamoto, T. Yakugaku Zasshi, 1973, 93,
1019; Chem. Abstr. 1973, 79, 105052c.
= 8.68 Hz), 7.39 (broad s, 2H, NH), 6.67 (d, 6-H, J6, = 8.80
7
Hz).
Amination of 2-nitroquinoline (1f). The amination of 1f was
carried out for 4 h according to general procedure. A small
amount of precipitate was filtered off and filtrate solution was
extracted by chloroform. After evaporation of solvent the
[21] Woꢃniak, M.; Grzegoꢀek, M. Liebigs Ann.Chem. 1993, 823.
[22] Tschitschibabin, A.E. Ber. Dtsch. Chem. Ges. 1923, 56, 1883.