Iron/acetic acid-mediated carbon degradation: A facile route for the synthesis of quinoline derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.07.063

A new carbon degradation protocol which results in the formation of quinoline derivatives is described. The reactions involved the use of mild reaction conditions and an inexpensive reducing reagent (Fe/AcOH).

Full text of DOI:10.1016/j.tetlet.2010.07.063

Tetrahedron Letters 51 (2010) 5234–5237
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Iron/acetic acid-mediated carbon degradation: a facile route for the synthesis
of quinoline derivatives
*
Chintakunta Ramesh, Veerababurao Kavala, Chun-Wei Kuo, Ching-Fa Yao
Department of Chemistry, National Taiwan Normal University, 88, Section 4, Tingchow Road, Taipei 116, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 April 2010
Revised 7 July 2010
Accepted 13 July 2010
Available online 16 July 2010
A new carbon degradation protocol which results in the formation of quinoline derivatives is described.
The reactions involved the use of mild reaction conditions and an inexpensive reducing reagent (Fe/
AcOH).
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
an important and useful task in organic chemistry and hence a
number of synthetic strategies including Skraup, Doebner–von
Degradation of carbon, a common phenomenon of the nature, is
also an efficient process for the synthesis of a large variety of or-
ganic molecules.1 Hoffman degradation, Curtius degradation, Ruff
degradation, and Kolbe electrolysis for the synthesis of hydrocar-
bons are well-known degradation reactions, where loss of carbon
atom(s) occurs during the product formation.2 Some of the re-
ported examples of carbon degradation during the formation of
synthetic and biomedically important products are depicted in
Scheme 1.3
Miller, Friedlander, Camps Combes, Conrad–Limpach–Knorr Gou-
ld–Jacobs reaction, and Meth–Cohn have been developed for the
construction of these ‘privileged’ structural motifs.12 Most of the
known procedures are associated with several short comings with
respect to the formation of side product(s) and the use of toxic sol-
vents and expensive catalysts. Hence the development of a more
convenient method for the synthesis of quinoline derivatives is still
a welcoming topic in organic synthesis.
In continuation to our work on Fe/AcOH-mediated reductive
cyclization of nitro derivatives,13 herein we report the synthesis
of quinolines through reductive degradation of Michael adducts
obtained from 1-nitro-2-(2-nitrovinyl)benzenes and ketones.
Fe/AcOH is an attractive reagent for the reduction of nitro group
due to its easy availability, environmental safety, and low cost. It
has been used as a reagent in reductive cyclization reactions in
the synthesis of aziridines, thieno[2,3-b][1,4]thiazin-2(3H)-one,
3,6-dimethyl-9H-4,5,9-triazaphenanthren-10-one, and pyrrolo-
[3,2-b] indole.4 Moreover, it is also being used in the preparation
of the chiral 3-substituted benzodiazepinone and pyrrolo[2,1-c]
2. Results and discussions
Recently, we reported the reaction of Michael adduct derived
from indole and 1-nitro-2-(2-nitrovinyl)benzene in the presence
[l,4]benzodiazepines derivatives.5
a-Methylene-c-butyrolactams
are very important pharmacological active compounds which can
also be synthesized by Fe/AcOH.6 In addition to these, the reagent
system was successfully applied to the synthesis of indole deriva-
tives.7 Furthermore, it is also being used in the synthesis of various
quinoline derivatives from Baylis–Hillman adducts.8
On the other hand, quinoline derivatives are well-known struc-
tural scaffolds in medicinal chemistry. These derivatives have been
found to possess useful pharmacological and biological activities
including antimalarial, antiasthmatic, antihypertensive, antibacte-
rial, and tyrosine kinase-inhibiting agents.9 In addition to these,
quinolines have been used for the preparation of nano- and meso-
structures with enhanced electronic and photonic properties.10
Moreover, quinoline-based polymers find applications in the fields
of electronics, optoelectronics, and nonlinear optics.11 All the
above-described facts indicate that the synthesis of quinolines is
Cat OsO4
NMM, NMO
R
R
O
O
NaIO4
Acetone / water
R'
R'
R''
R''
Br
COR
PPh3
(RCO)2O
NH2
Base / Heat
N
COR
NH2
N
-CXX'
Heat
X'
X'
+
R
R
R
+
N
H
X
NH2
X
X = NO2
, X' = H
X = CN X' = CN
,
* Corresponding author. Tel.: +886 2 29309092; fax: +886 2 29324249.
E-mail addresses: cheyaocf@ntnu.edu.tw, cheyaocf@yahoo.com.tw (C.-F. Yao).
Scheme 1. Examples of carbon degradation during the product formation.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.063

C. Ramesh et al. / Tetrahedron Letters 51 (2010) 5234–5237
5235
of Fe/AcOH to obtain the 3,30-bis-indoles in high yields.13b This re-
sult prompted us to study the reaction further by replacing indoles
with other C-nucleophiles such as ketones. We anticipated the for-
mation of 2-methyl-4-(nitromethyl)-3,4-dihydroquinoline deriva-
tives from the reductive cyclization of a Michael adduct derived
from 1-nitro-2-(2-nitrovinyl)benzene and acetone. Surprisingly
no trace of 2-methyl-4-(nitromethyl)-3,4-dihydroquinoline was
observed, rather the 2-methyl quinoline observed as the sole prod-
uct (Scheme 2). Being buoyant by this result we focused our atten-
tion to study this reaction with various 1-nitro-2-(2-nitrovinyl)
Table 1
The reaction of various Michael adducts with Fe/AcOH to form quinoline
derivatives15,16
O2N
O
Fe / AcOH
R
R'
R'
reflux, 2 h
N
R
NO2
Entry
1
Substratea
Product
Yield%b
79
O2N
O
1a
benzenes and a variety of ketones containing a-hydrogen.
N
In preliminary experiments, 4-nitro-3-(2-nitrophenyl)butan-2-
one was treated with Fe/AcOH at reflux for 2 h to obtain 2-methyl-
quinoline in excellent yield. To extend the scope of the reaction
further, we investigated the reaction of various Michael adducts
obtained from the reaction of 1-nitro-2-(2-nitrovinyl)benzene with
a variety of ketones. Under the present reaction conditions, the Mi-
chael adducts of a 1-nitro-2-(2-nitrovinyl)benzene and acyclic ke-
tones reacted to produce 2-alkyl quinoline derivatives in good
yields (Table 1).
NO2
O2N
O
O
2a
2
3
81
43
N
N
NO2
O2N
C4H9
3a
3b
C4H9
NO2
+
Regardless of the nature of the functional group present on the
phenyl moiety of the Michael adducts, we got a comparable yield
in all cases. On the other hand, an inseparable mixture of the Mi-
chael adducts was obtained from 1-nitro-2-(2-nitrovinyl)benzene
and heptan-2-one. This crude mixture was further treated with
Fe/AcOH at reflux for 2 h affording the corresponding two quino-
line derivatives, which were easily separated by column chroma-
tography. Unfortunately, we did not obtain the expected 4-
(nitromethyl)-3,4-dihydroquinoline derivatives in any of these
reactions. However, we obtained equally interesting and biological
important molecules such as 2-methyl quinoline derivatives.
Encouraged by the results obtained with Michael adducts of
acyclic ketones, we further investigated the reactions with the Mi-
chael adducts derived from the cyclic ketones with different 1-ni-
tro-2-(2-nitrovinyl) benzene derivatives. Analogous to the
previous case, the substitution on the aromatic ring had no influ-
ence on the outcome of the reaction, as systems substituted with
neutral (Table 2, entries 1, 4, 6, 7, and 9), electron-withdrawing
(entries 3 and 8), or electron-releasing groups (entries 2 and 5)
provided similar results. It is interesting to note that the reaction
of the five-membered and six-membered cyclic ketones similarly
provides the corresponding tricyclic compounds in good yields
(entries 1–6). The substrates containing oxygen and sulfur ring re-
mained intact under the present reaction condition. It is note wor-
thy that acid-sensitive group such as methoxy (entries 2 and 5)
survived under these conditions.
O2N
O
N
C5H11
41
C5H11
NO2
O2N
O2N
O
C6H5
4a
5a
4
5
6
7
8
9
85
82
83
83
80
80
N
C6H5
O
NO2
C6H5
N
C6H5
NO2
O2N
O
O
O
6a
O
O
N
NO2
O2N
BnO
BnO
O
7a
BnO
N
BnO
F
NO2
O
O2N
F
8a
N
NO2
O2N
O2N
Cl
Br
O
9a
Cl
Br
N
NO2
O
The mechanism for the formation of quinoline derivatives may
be through the reductive cyclization of 2-(2-nitro-1-(2-nitro-
phenyl)ethyl) cyclohexanone (1), and followed by loss of a nitro
methane or methylamine. The driving force here is aromatization
to form larger conjugated system. We envisioned two pathways
to form quinoline derivatives from 1 (Scheme 3). Among them
the first one involves the reduction of an aromatic nitro group to
amine in the presence of iron/acetic acid which further undergoes
10a
10
81
N
NO2
Starting materials were prepared by the known procedure.14
Isolated yields.
a
b
cyclization to form intermediate A. The intermediate upon losing
nitro methane forms the quinoline moiety. Another alternative ap-
proach may be in the presence of iron/acetic acid in which both the
nitro groups present in compound 1 reduce to its corresponding
amines followed by the cyclization to form intermediate B. The
intermediate B gets protonated and lose as the stable methyl
ammonium acetate to form quinoline derivatives. The details of
the mechanism are shown in Scheme 3.
Employing similar reaction conditions (Fe/AcOH) with 2-((2-
nitrophenyl) (2-oxocyclohexyl)methyl) malononitrile and di-
methyl 2-((2-nitrophenyl) (2-oxocyclohexyl)methyl) malonate
also afforded similar quinoline derivatives by the loss of a malon-
NO2
O2N
O
N
R
Fe / AcOH
reflux, 2 h
R
NO2
N
R
Scheme 2. Reaction of 4-nitro-3-(2-nitrophenyl)butan-2-one with Fe/AcOH.

5236
C. Ramesh et al. / Tetrahedron Letters 51 (2010) 5234–5237
Table 2
NC
CN
H
The reaction of various Michael adducts with Fe/AcOH to form tricyclic quinoline
derivatives15,16
O
Fe / AcOH
reflux, 2 h
CN
CN
O2N
O
N
N
X
Fe / AcOH
reflux, 2 h
NO2
14a (73 %)
R'
R'
I
n
N
n
NO2
X
COOMe
MeOOC
X = C, O, S n = 0, 1
O
COOMe
COOMe
II
Fe / AcOH
reflux, 2 h
H
H
Entry
1
Substratea
Product
Yield %b
83
N
NO2
N
O2N
O
11a
14a (75 %)
N
Scheme 4. Plausible mechanistic route for the formation of quinoline derivative.
NO2
O2N
O
O
O
12a
O
onitrile, dimethyl malonate, respectively, which is presented in
Scheme 4.
2
3
4
82
81
81
N
O
NO2
O
Itoh et al. reported that the reaction of benzylidene malononitr-
iles and b-nitrostyrenes with o-phenylene diamines in boiling eth-
anol produced the 2-phenylbenzimidazolines.3c In this reaction,
they found the elimination of nitromethane or malononitrile dur-
ing the product formation. Based on our experimental results and
the literature reports, we expect that both the pathways are possi-
ble for the formation of quinolines.
O2N
F
13a
N
N
NO2
O2N
O
14a
In conclusion, we have described a new degradation protocol
which results in the formation of quinoline derivatives. The overall
reactions involved the use of mild reaction conditions and an inex-
pensive reducing reagent (Fe/AcOH). The fact that the reactions
were clean and devoid of side reaction products constitutes addi-
tional attractive feature of this method. In summary, this method
finds an alternative procedure for the synthesis of quinoline deriv-
atives to the reported protocols.
NO2
O2N
O
O
O
O
15a
5
6
83
83
N
O
NO2
O2N
CH3
O
16a
N
Acknowledgments
NO2
CH3
O
Financial support for this work by the National Science Council
of the Republic of China and the National Taiwan Normal Univer-
sity is gratefully acknowledged.
O2N
O
17a
7
8
9
N
81
83
84
NO2
O2N
O
O
F
Supplementary data
O
18a
F
N
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.07.063.
NO2
O
O2N
O
S
19a
References and notes
N
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S
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.
a
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NO2
NO2
H
O
loss of
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path A
NO2
O
H2N
O
N
A
Fe / AcOH
reflux, 2 h
N
O2N
NH2
NH3
H
loss of
CH3NH3
Path B
H2N
N
b
Scheme 3. Plausible mechanistic route for the formation of quinoline derivative.

C. Ramesh et al. / Tetrahedron Letters 51 (2010) 5234–5237
5237
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15. To a stirred solution of 4-nitro-3-(2-nitrophenyl)butan-2-one 1 (1 mmol) in
acetic acid (5 mL), powdered Fe (6 mmol) was added and the reaction mixture
was refluxed for 2 h. The mixture was cooled to room temperature and the
acetic acid was removed under reduced pressure, EtOAc (10 mL) was added,
then the mixture was stirred for 2 min and then filtered to remove any iron
impurities. The insoluble iron residue was washed with EtOAc (10 mL). The
filtrate and washings were combined and dried over anhydrous MgSO4. The
solvent was removed under reduced pressure and the crude product was
purified by flash column chromatography (petroleum ether/ethyl acetate) to
yield the expected product.
16. Spectral data: 1,2,3,4-tetrahydroacridine (11a): White solid; mp: 46–48 °C. 1H
NMR (400 MHz, CDCl3) d 7.97 (d, J = 8.3 Hz, 1H), 7.79 (s, 1H), 7.68 (d, J = 8.0 Hz,
1H), 7.61–7.57 (m, 1H), 7.44–7.40 (m, 1H), 3.12 (t, J = 6.5 Hz, 2 H), 2.97 (t,
J = 6.1 Hz, 2H), 2.02–1.96 (m, 2H), 1.92–1.87 (m, 2H). 13C NMR (100 MHz,
CDCl3) d 159.0, 146.4, 134.8, 130.7, 128.3, 128.1, 127.0, 126.7, 125.3, 33.4, 29.0,
23.0, 22.7. MS (EI) (m/z) (relative intensity) 183(M+, 100), 182(40). HRMS calcd
for
C13H13N
(M+) 183.1043 found 183.1037. 8-Fluoro-3,4-dihydro-1H-
pyrano[4,3-b]quinoline (15a): White solid; mp: 107–109 °C. 1H NMR
(400 MHz, CDCl3) d 7.99 (dd, J = 8.2, 5.3 Hz, 1H), 7.70 (s, 1H), 7.45–7.40 (m,
1H), 7.34 (dd, J = 8.8, 2.6 Hz, 1H), 4.95 (s, 2H), 4.17 (t, J = 5.9 Hz, 2H), 3.21 (t,
J = 5.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) d 160.2 (d, J = 246.0 Hz), 154.4,
144.1, 130.9 (d, J = 10.0 Hz), 130.3 (d, J = 5.0 Hz), 129.5, 127.3 (d, J = 10.0 Hz),
119.4 (d, J = 26.0 Hz), 110.1 (d, J = 21.0 Hz), 67.7, 65.9, 32.6. MS (EI) (m/z)
(relative intensity) 203 (M+, 100), 173(27). HRMS calcd for C12H10FNO (M+)
203.0741 found 203.0735.