An efficient synthesis of nitrated cycloalka[ b ]pyridines

Article abstract of DOI:10.1055/s-0033-1341237

The three-component ring transformation of 1-methyl-3,5-dinitro-2-pyridone with cycloalkanones of different ring sizes in the presence of ammonium acetate affords the corresponding nitrated cycloalka[b]pyridines in high yields. Furthermore, a double bond can be easily introduced into the product by changing the cycloalkanone into a cycloalkenone. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1341237

PAPER
▌2175
paper
An Efficient Synthesis of Nitrated Cycloalka[b]pyridines
Nitrated Cycloalka[b]pyridines
a
a,b
a
School of Environmental Science and Engineering, Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502, Japan
Fax +81(887)572520; E-mail: nishiwaki.nagatoshi@kochi-tech.ac.jp
b
Research Center for Material Science and Engineering, Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502, Japan
Received: 27.02.2014; Accepted after revision: 26.03.2014
ketones 2 in the presence of NH OAc afforded the nitro-
4
Abstract: The three-component ring transformation of 1-methyl-
pyridines 3 in good to excellent yields (Scheme 1,
3,5-dinitro-2-pyridone with cycloalkanones of different ring sizes
7
method b). This TCRT is advantageous in terms of the
in the presence of ammonium acetate affords the corresponding ni-
trated cycloalka[b]pyridines in high yields. Furthermore, a double use of solid NH4OAc compared to gaseous ammonia, and
bond can be easily introduced into the product by changing the cy- extra NH OAc can be easily removed from the reaction
4
cloalkanone into a cycloalkenone.
mixture by thermal decomposition. The successful results
Key words: pyridines, multicomponent reaction, ketones, hetero- of our study prompted us to extend the substrate scope of
cycles, bicyclic compounds, ring transformation
this method to a series of cyclic ketones 4. Thus, nitrated
cycloalka[b]pyridines 5 could be obtained and further em-
ployed as useful intermediates for the synthesis of meta-
4
8
Compounds containing nitro groups are widely used in or- cyclophanes, pharmacophores, and biologically active
9
ganic syntheses because of their diverse range of reactiv- compounds.
1
ities. We have reported a synthetic method that can be
used to generate arylated nitropyridines 3 by the three-
component ring transformation (TCRT) of dinitropyri-
done 1 with aromatic ketones 2 in the presence of ammo-
The reaction of the dinitropyridone 1 with cyclohexanone
a in the presence of NH OAc (5 equiv) at 65 °C for 24
4
4
2b,4b,10
hours afforded nitrated cyclohexa[b]pyridine 5a
in a
moderate yield; the disappointing yield was because of the
2
nia, in which 1 serves as the synthetic equivalent of
shortage of nitrogen source due to competitive thermal de-
3
unstable nitromalonaldehyde (Scheme 1, method a). Re-
cently, other research groups also reported the TCRT of 1
with ketones by using ammonia as the nitrogen source.
7
composition of NH OAc (Table 1, entry 1). This problem
4
was easily solved by increasing the amount of NH OAc,
4
4
and the yield of 5a could be increased to 95% (entries 2
and 3). When microwave heating was used, nitropyridine
Although these methods provide easily access to nitropy-
ridine derivatives in a single step, they suffer from low
product yields because of competitive ammonolysis of
5a was afforded efficiently within one hour (entry 4). Cy-
clopentanone 4b was less reactive than 4a, thus affording
5
substrate 1. Furthermore, methanolic ammonia should be
2b,10
cyclopentapyridine 5b
in only 67% yield under the
prepared in advance, which is also troublesome.
same reaction conditions (entry 5). In such a case, micro-
wave heating was particularly effective, and the reaction
reached completion within a short time under microwave
heating (entries 6 and 7). In contrast, larger cycloal-
kanones 4c and 4d underwent the TCRT efficiently to af-
Me
O
NO2
O
R
NO2
NO2
N
NH3
R
R
+
(
a)
Ar
Ar
MeOH
Ar
N
3
2
2
NO2
ford
cyclooctapyridines 5c and 5d,
−11). When unsymmetrical 2-methylcyclohexanone 4e
the
corresponding
cyclohepta-
respectively (entries
and
1
10
4b,10
8
O
Me
O
NO2
+
R
NH4OAc
EtOH
was employed, 8-methylated tetrahydroquinoline 5e was
obtained efficiently (entries 12 and 13). The reaction con-
ditions were also applied to unsaturated cyclic ketone 4f,
thus affording 7,8-dihydroquinoline 5f, although micro-
wave heating was again necessary for efficient TCRT (en-
tries 14−16). In contrast, cylopentenone 4g did not
N
(b)
Ar
N
3
NO2
1
Scheme 1 Synthetic methods for 2-arylated 5-nitropyridines 3 by
TCRT of dinitropyridone 1 with aromatic ketones 2 in the presence of undergo TCRT despite the application of microwave heat-
a nitrogen source
ing (entry 17).
A plausible mechanism for this TCRT is shown in
These disadvantages were overcome by using less nucle- Scheme 2. After addition of the enol form of 4a to the 4-
ophilic ammonium acetate (NH OAc) instead of ammo- position of 1, the resulting adduct 6a is transformed into
4
6
nia. The reaction of dinitropyridone 1 with aromatic enanine 7a by reaction with an ammonium ion. Intramo-
lecular attack of the amino group at the 6-position affords
tricyclic intermediate 8a, from which nitroacetamide is
SYNTHESIS 2014, 46, 2175–2178
Advanced online publication: 08.05.2014
eliminated to afford nitropyridine 5a after the aromatiza-
tion of intermediate 9a. Although another reaction path
via enamine 10a can be considered, the same product 5a
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1341237; Art ID: ss-2014-f0139-op
Georg Thieme Verlag Stuttgart · New York
©

2176
T. S. Le et al.
PAPER
Table 1 Synthesis of Cycloalka[b]pyridines 5 by TCRT
Me
O
NO2
NO2
N
NH OAc
4
+
O
EtOH
n
n
N
65 °C
NO2
5
4
1
Entry
n
Ketone
NH OAc
Time
(h)
Product
Yield
(%)
4
(
equiv)
1
2
3
4
5
24
24
24
56
88
95
97
NO2
NO2
10
15
15
2
4a
5a
O
O
a
N
1
5
6
7
15
15
15
24
2
1
67
87
70
a
1
3
4b
4c
5b
5c
a
N
NO2
8
9
15
15
24
1
94
91
O
a
N
NO2
1
1
0
1
15
15
24
1
85
95
4
2
4d
4e
5d
5e
a
N
O
NO2
1
1
2
3
15
15
24
2
83
86
a
O
N
N
NO2
NO2
1
1
1
4
5
6
15
15
15
24
3
1
59
89
40
a
2
1
4f
5f
a
O
O
1
7
4g
15
4a
5g
0
N
a
Microwave heating was used.
HO
H
NH3
NO2
NO2
H
4
a
O
H2N
2
O2N
NO2
O
2
O N
NO2
O N
NO2
N
H
O
N
N
N
O
N
O
Me
Me
Me
8a
Me
1
6a
7a
O
Me
NO2
N
H
H2N
O2N
NO2
NO2
NO2
O
5
a
N
N
H
5a
N
9a
Me
1
0a
Scheme 2 A plausible mechanism for the formation of condensed nitropyridine 5a
Synthesis 2014, 46, 2175–2178
© Georg Thieme Verlag Stuttgart · New York

PAPER
Nitrated Cycloalka[b]pyridines
2177
is formed. In the case of unsymmetrical 2-methylcyclo- The melting points were determined with a Yanaco micro-melting-
1
point apparatus, and are uncorrected. H NMR spectra were mea-
hexanone (4e), two kinds of intermediates, 8e and 8e′, are
possible (Scheme 3); however, the latter intermediate can-
not afford the aromatized product. Therefore, only 5e is
formed via intermediate 8e. In the reactions using cyclo-
sured with a Bruker Ascend-400 at 400 MHz, with TMS as internal
13
standard. C NMR spectra were measured with a Bruker Ascend-
00 at 100 MHz, and assignment was made on the basis of DEPT
experiments. The IR spectra were recorded with a JASCO FT/IR-
4
pentanone (4b) and cyclohex-2-enone (4f), the loss of 4200 spectrophotometer. The high-resolution mass spectra were
flexibility of 7b and 7f makes the formation of tricyclic in- measured with a JEOL JMS-DX303HF. Microwave heating was
performed with an Anton-Paar Microwave 300. All the reagents and
solvents were commercially available and were used as received.
termediates 8b and 8f more difficult (Scheme 4). In con-
trast, cyclopentenone 4g did not afford the ring-
transformed product 5g because, in this case, the forma-
tion of a sterically restricted intermediate is necessary.
TCRT; Typical Procedure
To a solution of the dinitropyridone 1 (50 mg, 0.25 mmol) in EtOH
(
5 mL), cyclohexanone 4a (26 μL, 0.25 mmol) and NH OAc (289
4
mg, 3.75 mmol) were added, and the resultant mixture was heated
at 65 °C on an oil bath for 24 h. After removal of the solvent, the
residue was washed with benzene (3 × 10 mL) to afford 5,6,7,8-tet-
rahydro-3-nitroquinoline (5a; 42 mg, 0.24 mmol, 95%) as a yellow
powder. The reactions of dinitropyridone 1 with other ketones 4b–g
were performed in a similar way. When the reaction was conducted
using microwave heating, the procedure was analogous.
Me
H
NO2
NO2
H2N
O2N
NO2
O
N
N
H
O
N
Me
Me
6,7-Dihydro-3-nitro-5H-cyclopenta[b]pyridine (5b)2b,10
Yield: 43 mg (97%); yellow powder.
Me
7e
8e
6
,7,8,9-Tetrahydro-3-nitro-5H-cyclohepta[b]pyridine (5c)10
Yield: 36 mg (87%); yellow powder.
H
NO2
NO2
H2N
O2N
5,6,7,8,9,10-Hexahydro-3-nitrocycloocta[b]pyridine (5d)4b,10
Me
Me
NO2
O
Yield: 49 mg (95%); yellow powder.
5
,6,7,8-Tetrahydro-8-methyl-3-nitroquinoline (5e)10
N
N
H
O
N
Yield: 41 mg (86%); yellow powder.
Me
Me
7e'
8e'
7,8-Dihydro-3-nitroquinoline (5f)
Yield: 40 mg (89%); yellow powder; mp 57–59 °C.
Scheme 3 Two plausible intermediates derived from 1-methylcyclo-
hexanone 4e
IR (KBr): 1261, 1577, 1509 cm–1.
1
H NMR (CDCl ): δ = 2.49 (ddt, J = 2.8, 4.0, 8.4 Hz, 2 H), 2.99 (t,
3
J = 8.4 Hz, 2 H), 6.57 (dt, J = 4.0, 8.0 Hz, 1 H), 6.74 (ddt, J = 0.8,
2
.8, 8.0 Hz, 1 H), 8.16 (dd, J = 0.8, 2.8 Hz, 1 H), 9.19 (d, J = 2.8 Hz,
H
NO2
1 H).
H2N
NO2
13
C NMR (CDCl ): δ = 22.6 (CH ), 26.5 (CH ), 128.9 (CH), 129.3
3
2
2
O2N
NO2
O
(CH), 131.3 (C), 139.1 (CH), 141.1 (C), 143.3 (CH), 158.8 (C).
HRMS (EI): m/z calcd for C H N O : 176.0586; found: 176.0586.
N
N
H
O
9
8
2
2
N
Me
Me
7b
8b
Acknowledgment
We sincerely thank Prof. Satoshi Minakata (Osaka University, Ja-
pan) for his kind assistance.
H
NO2
NO2
H2N
O2N
Supporting Information for this article is available online
NO2
O
at
http://www.thieme-connect.com/products/ejournals/journal/
1
0.1055/s-00000084. SunogIpimirf antoSuIpg
n
ori
m
N
N
O
N
Me
H
Me
7f
8f
References
Scheme 4 The intermediate 7b and 7f
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2
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©
Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2175–2178

2
178
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in the presence of NH OAc proceeds efficiently to afford
4
pyrimidines, nitropyridones, and aminopyridines, see:
Synthesis 2014, 46, 2175–2178
© Georg Thieme Verlag Stuttgart · New York