Novel functionalization of 1-methyl-2-quinolone; dimerization and denitration of trinitroquinolone

Article abstract of DOI:10.1016/S0040-4020(01)01169-3

New methods for functionalization of 1-methyl-2-quinolone (MeQoe) skeleton are provided. The reaction of 1-methyl-3,6,8-trinitro-2-quinolone (TNQ) with amines affords quinolone dimer 1 and 6,8-dinitroquinolone (6,8-DNQ). Dimerization predominantly proceed

Full text of DOI:10.1016/S0040-4020(01)01169-3

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 473±478
Novel functionalization of 1-methyl-2-quinolone; dimerization
and denitration of trinitroquinolone
a,p
Nagatoshi Nishiwaki, Midori Sakashita, Mayumi Azuma, Chitose Tanaka, Mina Tamura,
a
a
a
a
b
Noriko Asaka, Kazushige Hori, Yasuo Tohda and Masahiro Ariga
c
c
a,p
a
Department of Chemistry, Osaka Kyoiku University, Asahigaoka 4-698-1, Kashiwara, Osaka 582-8582, Japan
Center for Instrumental Analysis, Osaka Kyoiku University, Asahigaoka 4-698-1, Kashiwara, Osaka 582-8582, Japan
b
c
Division of Natural Science, Osaka Kyoiku University, Asahigaoka 4-698-1, Kashiwara, Osaka 582-8582, Japan
Received 24 October 2001; accepted 21 November 2001
AbstractÐNew methods for functionalization of 1-methyl-2-quinolone (MeQone) skeleton are provided. The reaction of 1-methyl-3,6,8-
trinitro-2-quinolone (TNQ) with amines affords quinolone dimer 1 and 6,8-dinitroquinolone (6,8-DNQ). Dimerization predominantly
proceeds at room temperature, and denitration takes place under heated and diluted conditions. We also provide a plausible mechanism
for these reactions on the basis of structure±reactivity relationship of amines. q 2002 Elsevier Science Ltd. All rights reserved.
1
. Introduction
tives functionalized at the 3- and 4-positions. In our course
of study on another strategy, we have shown that 1-methyl-
3,6,8-trinitro-2-quinolone (TNQ) is an excellent synthetic
intermediate for direct functionalization of MeQone. TNQ
attains high reactivity with steric strain resulting from
repulsion between 8-nitro and 1-methyl groups besides
The 1-methyl-2-quinolone (MeQone) skeleton is seen in
more than 300 quinoline alkaloids isolated from the
Rutaceae family,1 and the isolation, the structural deter-
mination and total syntheses of new quinoline alkaloids
±3
2
5
4
±10
containing MeQone are still active area.
From the view-
electron-de®ciency. The C±C bond is regioselectively
formed at the 4-position with loss of an adjacent nitro
group (cine-substitution) when TNQ is treated with 1,3-di-
point of biochemical and pharmacological interests,
researcher's attention is recently turned to not only study
on natural products but also preparation of unnatural
compounds having the MeQone framework as the partial
Thus, it is highly demanded to develop new
methods for both functionalization
MeQone derivatives.
2
6
carbonyl compounds in the presence of triethylamine. This
reaction proceeds in the addition±elimination mechanism,
in which nitrous acid is eliminated from the adduct inter-
mediate, 3,4-dihydroquinolone, as illustrated in Scheme 1.
1
1±17
structure.
1
8,19
20
and construction of
On the other hand, quite different reactivity is observed in
the reaction of TNQ with amine in the absence of nucleo-
phile, namely, dimerization and denitration proceed. Since
these transformations will be novel procedures for
functionalization of the MeQone skeleton, we have screened
The cycloaddition of the a,b-unsaturated carbonyl moiety
in the MeQone skeleton has been employed for this
purpose.2
ring-fused systems, which are converted to MeQone deriva-
1±24
It is possible to prepare various kinds of
Scheme 1.
Keywords: trinitroquinolone; nitration; denitration; dimerization; cine-substitution.
Corresponding authors. Tel.: 181-729-78-3398; fax: 181-729-78-3399; e-mail: ariga@cc.osaka-kyoiku.ac.jp
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)01169-3

4
74
N. Nishiwaki et al. / Tetrahedron 58 (2002) 473±478
under various conditions
Table 1. Reactions of TNQ with NBu
3
3
Solvent (cm )
a,b
c
Run
1
Temperature (8C)
Time (d)
1/6,8-DNQ
Yield (%)
b
1
6,8-DNQ
d
rt
10
1
10
50
30
50
7
63/37
88/1281
6
2
3
4
5
6
60
10
80
e
1
7
1
1
40/60
d
rt
82/18
25/75
25/75
60
60
20
58
a
b
c
d
e
1
Determined by H NMR.
Based on TNQ.
Isolated yield.
Room temperature.
Reaction mixture was somewhat complicated.
reaction conditions using several kinds of amines. A
plausible mechanism for these reactions is also presented
here on the basis of structure±reactivity relationship of
amines.
by comparison of spectral data with those of authentic
sample.
The ratio of products (1/6,8-DNQ) varies with reaction
conditions as summarized in Table 1. In each case, TNQ
is quantitatively consumed without detection of by-product
except for run 3. 6,8-DNQ is predominantly formed under
heated conditions (runs 2and 3). Dilution is considerably
effective to prevent the dimerization affording 6,8-DNQ in a
good yield (runs 5 and 6).
2
. Results and discussions
The reaction of TNQ with tributylamine at room tempera-
ture afforded 3,4 -bis(1-methyl-6,8-dinitro-2-quinolone) (1)
0
and 6,8-dinitro-1-methyl-2-quinolone (6,8-DNQ) in 81
2
5
1
and 6% yields, respectively (Table 1, run 1). In the H
When MeQone is directly nitrated, the nitro groups are
introduced in the order of 6-.3-ù8-positions. Since the
3-position is somewhat rapidly nitrated than the 8-position,
the preparation of 6,8-DNQ is more dif®cult than that of 3,6-
DNQ. Only mononitration proceeds without formation of
DNQs at low temperature (Table 2, run 1). At a little higher
temperature, 6,8-DNQ and 3,6-DNQ are produced, but
separation of four nitroquinolones is very troublesome
because of similar property (runs 2and 3). As MeQone is
NMR of dimer 1, two singlet signals were observed at
7
.06 and 8.56 ppm in addition to two pairs of doublets
0 0
(
H5, H7, H5 and H7 protons) and two singlets (N-methyl
groups). This observation revealed that a couple of 1,2-
dihydro-6,8-dinitro-1-methyl-2-oxoquinolyl groups con-
0
nected at the 3- and the 4 -positions. Analytical and other
1
3
spectral data (IR, MS, C NMR) also supported this
dimeric structure. The structure of 6,8-DNQ was con®rmed
Table 2. Nitration of MeQone leading to four nitroquinolones
a
Run Temperature (8C) Time (d)
Yield (%)
6
,8-DNQ 3,6-DNQ TNQ 6-NQ
1
2
3
4
5
50
5
61 0
5
7
0 7
0
4 2 19
0
0
72
70
5
80
120
12
29
0
0
41
0
0
8
63
90
18
0
0
b
a
1
Run 1,2,5: isolated yield, run 3,4: determined by H NMR.
b
MeQone was heated in fuming HNO
3
(dˆ1.52).

N. Nishiwaki et al. / Tetrahedron 58 (2002) 473±478
475
effectively converted to TNQ under severe conditions (run
), the present denitration reaction affords 6,8-DNQ more
easily in an improved yield than the direct nitration of
MeQone.
region. There are large differences of reactivity among
amines (Fig. 1). When trimethylamine and tribenzylamine
are used, TNQ was quantitatively recovered without
changing. Amines substituted with longer alkyl chains
caused the dimerization, and the reaction using tributyl-
amine proceeds much faster than the cases of tripropyl-
and triethylamines. However, tertiary amines having one
long chain is unexpectedly less reactive. Butyldimethyl-
amine and other alkyldimethylamines afford dimer 1 in
only poor yields (Table 3). On the contrary, dibutylmethyl-
amine undergoes as effectively as tributylamine. Hence,
more than two long alkyl chains are found to be necessary
in the present reaction.
5
Isolated dimer 1 is stable not leading to 6,8-DNQ under
heated conditions (at 608C, in the presence of tributyl-
amine). In addition, 6,8-DNQ and tributylamine furnish no
dimer 1 at room temperature. Since interconversion between
1 and 6,8-DNQ does not proceed, one product is found not
to be an intermediate of the other product.
Trialkylamine often behaves as the single electron donor in
the photochemistry, but this reaction is unrelated to the
light. Dimer 1 and 6,8-DNQ are similarly obtained in both
cases in the dark and under UV irradiation. The presence of
the electron acceptor, anthracene or benzophenone, also has
no in¯uence on the reaction, and they remain unchanged.
When metal (sodium, magnesium) and copper(I) salts are
used instead of amine, TNQ is intact to be recovered. We
obtained no evidence that single electron transfer from
amine to TNQ initiates the reaction.
The above results encouraged us to employ secondary and
primary amines instead of tertiary ones. In the case of
dibutylamine, conversion from TNQ to dimer 1 is smoothly
performed. Importantly, this reaction is also caused by
secondary amine, which has two long alkyl chains. Even
diethylamine affords dimer 1 more effectively than tertiary
amines shown in Table 3 (Scheme 2).
Several tertiary amines are employed, and the reaction
mixture is monitored with H NMR. In each case, only
signals of TNQ and dimer 1 are observed in the aromatic
1
Scheme 2.
On the other hand, butylamine shows interesting reactivity.
Ammonium salt of Meisenheimer complex 2 is immediately
precipitated as yellowish solid just after addition of butyl-
amine. When a suspension of isolated salt in acetonitrile is
heated at 608C for 1 day, small amount of dimer 1 and 6,8-
DNQ are furnished while the greater part of the salt is
reversed to TNQ (Scheme 3). These facts suggest that
Figure 1. Comparison of reaction rates using three amine homologs.
Table 3. Reaction of TNQ with dimethylamines having a long alkyl chain
a
a
R
Yield 1 (%)
Recovery TNQ (%)
Butyl
18
22
19
31
82
78
81
69
Pentyl
i-Pentyl
Hexyl
a
1
Determined by H NMR.
Scheme 3.

476
N. Nishiwaki et al. / Tetrahedron 58 (2002) 473±478
Meisenheimer complex, the adduct of TNQ with amine, is a
key intermediate in both dimerization and denitration.
As a result of various trials, N-nitrosodibutylamine 3 could
be isolated with column chromatography on silica gel. The
spectral data of 3 conform to those of the authentic sample
prepared by nitrosoation of dibutylamine with nitrous
2
7
acid. Taking this result into consideration, a plausible
mechanism for these two kinds of reactions is illustrated
in Scheme 4. Tributylamine attacks at the electron de®cient
4
-position of TNQ leading to Meisenheimer complex 4,
Figure 2.
from which b-elimination proceeds with release of 1-butene
to afford dihydroquinolone 5. Under heated conditions, 6,8-
DNQ is formed with elimination of dibutylamino and
nitro groups as nitroamine. When dihydroquinolone 5 is
converted to zwitter ion 6 with proton transfer from
dibutylamine with nitrous acid or a reduced product of
nitroamine by nitrous acid. In the case of diethylamine, it
cannot be ignored competitive nitrosoation proceeds before
the addition of amine to TNQ and successive dimerization.
3
-position to adjacent dibutylamino group, cine-substitution
of salt 6 and unreacted TNQ proceeds to give dimer 1 via 7.
Steric hindrance of dimeric adduct 7 assists elimination of
nitrous acid and prevents further oligomerization. Nitro-
soamine 3 is considered to be a nitrosoated product of
The structure±reactivity relationship of amines is ration-
alized as follows. The key step of the present reaction is
the intramolecular prototropy of Meisenheimer complex 4
accompanied with elimination of an alkyl chain on the
amino group as the alkene. Since trimethylamine and tri-
benzylamine have no b-hydrogen, only elimination of
tertiary amine from the adduct proceeds to give TNQ. In
the cases of alkyldimethylamines and primary amine, the
alkyl chain avoids steric repulsion with adjacent nitro group
(Fig. 2, structure 4a), and the suitable conformation for
b-elimination is hardly present. On the other hand, one of
alkyl chains surely locates nearby the 3-nitro group when
the amino group has more than two alkyl groups (Fig. 2,
structure 4b). Hence, amine should have proper steric bulk
for the smooth reaction. The different reactivity between
triethyl-, tripropyl- and tributylamines supports this
speculation.
3. Conclusion
In this paper, two novel methods for functionalization of the
MeQone skeleton are provided. The choice of reaction path
whether dimerization or denitration is easily performed by
varying reaction temperature and concentration of
substrates. Denitration is more competent method for
preparation of 6,8-DNQ than the direct nitration of
MeQone. The present reactions are caused by tertiary and
secondary amines having more than two long alkyl chains.
On the basis of the structure±reactivity relationship of
amines, we suggest the b-elimination of 4 with release of
alkene affording 5 is a key step.
4. Experimental
4.1. General
The melting points were determined on a Yanaco micro-
melting-points apparatus, and were uncorrected. All the
reagents and solvents were commercially available and
1
13
used as received. H and C NMR spectra were measured
on a Bruker DPX-400 at 400 and at 100 MHz with TMS as
an internal standard. IR spectra were recorded on a Horiba
FT-200 IR spectrometer. Mass spectrum was recorded on a
Scheme 4.

N. Nishiwaki et al. / Tetrahedron 58 (2002) 473±478
477
2
5
JEOL JMS-AX505HA. Elemental microanalyses were
performed using a Yanaco MT-3 CHN corder.
4.5.3. 1-Methyl-6-nitro-2-quinolone (6-NQ). d 3.65 (s,
3H), 6.75 (d, Jˆ9.6 Hz, 1H), 7.68 (d, Jˆ9.3 Hz, 1H), 8.09
(
d, Jˆ9.6 Hz, 1H), 8.53 (dd, Jˆ9.3, 2.3 Hz, 1H), 8.68 (d,
Jˆ2.3 Hz, 1H).
4
.2. 1-Methyl-3,6,8-trinitro-2-quinolone (TNQ)
2
6
4
.5.4. TNQ. d 3.42(s, 3H), 9.04 (d, Jˆ2.7 Hz, 1H), 9.24
MeQone was prepared by oxidation of 1-methylquinolinium
ion using K [Fe(CN) ] under alkaline conditions after
methylation of quinoline with dimethyl sulfate. Nitration
(d, Jˆ2.7 Hz, 1H), 9.26 (s, 1H).
3
6
1
.6. Dimerization with monitoring by H NMR
4
of MeQone with fuming nitric acid (dˆ1.52) afforded
2
6
TNQ in 90% yield.
To a solution of TNQ (29.4 mg, 0.1 mmol) in CD CN
3
3
0.3 cm ), trialkylamine (0.1 mmol) was added, and the
(
solution was stood at 258C. The monitoring was performed
4
.3. Amines
1
with H NMR at interval of a few or several hours. Since no
Amines were commercially available and used as received.
Methylamines and dimethylamines were prepared from
corresponding amines by methylation with formaldehyde
other signal than TNQ and dimer 1 was observed in the
aromatic region, the integral ratio of 1/(TNQ11) could be
regarded as the conversion and yield of 1. Reactions of TNQ
with alkyldimethylamines were also conducted in a similar
way.
2
8
in the presence of formic acid.
.4. Reaction of TNQ with tributylamine
To a solution of TNQ (294 mg, 1 mmol) in acetonitrile
4
4.7. Reaction of TNQ with butylamine
3
3
(
10 cm ), tributylamine (0.24 cm , 1 mmol) was added.
To a solution of TNQ (294 mg, 1 mmol) in acetonitrile
(
After stirring at room temperature for 7 days, the mixture
was concentrated under reduced pressure. The residue was
treated with column chromatography on silica gel (eluent:
3
10 cm ), butylamine (0.10 cm , 1 mmol) was added at
3
room temperature. When amine was added, yellowish
solid was immediately precipitated. After stirring for 3 h,
the solid was collected by ®ltration (220 mg, 0.5 mmol,
quantitatively obtained based on amine).
CHCl /ethyl acetateˆ9/1) to afford dimer 1 (193 mg,
3
0
.41 mmol) and 6,8-DNQ (14 mg, 0.06 mmol). In other
reactions under different conditions or reactions using
other amines, experiments were conducted similarly.
4.7.1. Butylammonium salt of 4-butylamino-3,4-di-
hydro-1-methyl-3,6,8-trinitro-2-quinolone 2. Since this
0
yellow powder; mp 288±2918C (dec.); IR (Nujol) 1662,
4
.4.1. 3,4 -Bis(1-methyl-6,8-dinitro-2-quinolone) (1). Pale
salt was not stable under ambient conditions to give TNQ
and it was too hygroscopic, only H NMR could be
1
2
554, 1346 cm ; H NMR (DMSO-d ) d 3.41 (s, 3H),
1
1
1
measured. H NMR (DMSO-d ) d 0.7±1.0 (br, 6H), 1.2±
1
3
1
(
(
6
6
.43 (s, 3H), 7.06 (s, 1H), 8.56 (s, 1H), 8.57 (d, Jˆ2.5 Hz,
1
.7 (br, 8H), 2.8±3.6 (br, 10H), 5.2±5.6 (br, 1H), 8.3±8.7
H), 8.95 (d, Jˆ2.5 Hz, 1H), 9.02 (d, Jˆ2.6 Hz, 1H), 9.10
(br, 2H).
1
3
d, Jˆ2.6 Hz, 1H); C NMR (DMSO-d ) d 34.7 (q), 34.7
6
q), 122.0 (s), 122.6 (d), 122.7 (d), 122.7 (d), 124.6 (s),
1
26.1 (s), 128.4 (d), 129.4 (s), 137.3 (s), 137.5 (s), 137.7
s), 138.2(s), 140.1 (d), 140.2(d), 140.3 (s), 145.0 (s), 160.8
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