Simultaneous Double C2/C3 Functionalization of Quinoline with p-Nitrobenzoyl(phenyl)acetylene. One-Pot Synthesis of 3-(4-Nitrobenzoyl)-2-phenylquinoline

Article abstract of DOI:10.1134/S1070428018120205

4-Nitrophenyl)(2-phenylquinolin-3-yl)methanone has been synthesized in one step by simultaneous double C²/C³ functionalization of the pyridine ring of quinoline molecule by the action of p-nitrobenzoyl(phenyl)acetylene in aqueous pot

Full text of DOI:10.1134/S1070428018120205

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 12, pp. 1845–1847. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © K.V. Belyaeva, L.P. Nikitina, A.V. Afonin, B.A. Trofimov, 2018, published in Zhurnal Organicheskoi Khimii, 2018, Vol. 54, No. 12,
pp. 1830–1832.
SHORT
COMMUNICATIONS
2
3
Simultaneous Double C /C Functionalization of Quinoline
with p-Nitrobenzoyl(phenyl)acetylene. One-Pot Synthesis
of 3-(4-Nitrobenzoyl)-2-phenylquinoline
a
a
a
a
K. V. Belyaeva , L. P. Nikitina , A. V. Afonin , and B. A. Trofimov *
a
Favorskii Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
*
e-mail: boris_trofimov@irioch.irk.ru
Received May 8, 2018; revised November 14, 2018; accepted November 16, 2018
Abstract—(4-Nitrophenyl)(2-phenylquinolin-3-yl)methanone has been synthesized in one step by simulta-
2
3
neous double C /C functionalization of the pyridine ring of quinoline molecule by the action of p-nitroben-
zoyl(phenyl)acetylene in aqueous potassium hydroxide.
DOI: 10.1134/S1070428018120205
In recent time, increased interest has been observed
in reactions of azines with electron-deficient acety-
lenes, which involve reversible formation of 1,3-di-
poles (zwitterions), namely vinylic carbanions with
an ammonium counterion located in the same mole-
cule. Depending on the azine structure and acetylene
nature, such reactions are accompanied by ring open-
ing [1–4], ring expansion [5], functionalization [6], or
fusion to another heterocyclic system [7, 8]. An im-
portant advantageous feature of this approach is that it
makes it possible to carry out the reactions under mild
conditions, often at room temperature, generally in the
absence of a catalyst (less frequently, in the presence
of bases). As a result, the final products can be
obtained with enhanced selectivity and high purity,
without transition metal impurities. This is important
for potential pharmaceuticals [9] which usually include
functionalized and fused azines.
acetyl)acetylenes at –18 to 25°C [8] (Scheme 1).
However, quinoline (1) reacted with p-nitrobenzoyl-
(phenyl)acetylene (2) in the presence of 20 mol % of
potassium hydroxide in water (55–60°C, 24 h) in
a quite different way, unexpectedly yielding 24% of
3-(4-nitrobenzoyl)-2-phenylquinoline (3) (Scheme 2).
The yield of 3 was lower (19%) when the reaction was
carried out in 70% aqueous acetonitrile for a longer
time (48 h), and the reaction mixture contained hy-
droxy enone 4 resulting from base-catalyzed hydration
[10] of 2. Compound 4 was isolated in 11% yield as
a mixture of two tautomers 4a and 4b, both having
Z-configured double bond (Scheme 3). This reaction,
as well as other possible base-catalyzed side processes
involving electron-deficient acetylene derivative, in
particular its anionic polymerization, are likely to be
responsible for the low yield of functionalized
quinoline 3.
We have recently reported a noncatalytic one-step
procedure for the stereoselective synthesis of
functionalized hydroxy(trifluoromethyl)oxazinoquino-
lines by reaction of quinolines with aryl(trifluoro-
Formalistically, the observed functionalization can
be regarded as replacement of an unsubstituted
acetylene molecule in the pyridine ring of quinoline by
the disubstituted alkyne fragment. However, no any
Scheme 1.
O
H O, MeCN
H
2
R
–
18 to 25°C
R
+
N
O
CF3
up to 99%
N
OH
CF3
Ar
Ar
1
845

1
846
BELYAEVA et al.
Scheme 2.
O
O
5
8
2'
KOH (20 mol %), H O
2
3
1'
3'
5
5–60°C, 24 h
+
2
6
'
Ph
4'
N
N
Ph
NO2
NO2
5'
1
2
3
Scheme 3.
OH
O
O
O
O
OH
3
KOH, H O
1'
2
1
3'
2
Ph
Ph
Ph
2
NO2
NO2
NO2
5'
4
a
4b
acetylene traces were detected in the reaction mixture.
Obviously, the reaction is a complex tandem process
initiated by 1,3-dipolar adduct A derived from quino-
line and electron-deficient acetylene 2 (Scheme 4).
After neutralization of the carbanionic center by proton
from a water molecule, quinolinium hydroxide B in
its covalent form C undergoes rearrangement with
opening of the pyridine ring by analogy with [1, 2].
Base-catalyzed prototropic shift in intermediate
N-vinyl aldehyde D gives imine E, and intramolecular
Michael addition of the activated methylene group in
the latter to the α,β-unsaturated aldehyde fragment
closes dihydroquinoline ring to form intermediate F.
Elimination of acetaldehyde molecule from F yields
substituted quinoline 3. The proposed scheme was con-
firmed by the detection of acetaldehyde in the reaction
mixture by mass spectrometry.
The described one-pot synthesis of quinoline 3 is
2
3
the first example of simultaneous double C /C func-
tionalization of the pyridine fragment of quinoline
molecule with p-nitrobenzoyl(phenyl)acetylene. It
cannot be ruled out that the observed cascade process
may be general for some quinolines and electron-
deficient acetylenes. We hope to answer this question
in the course of further study of this reaction.
(
4-Nitrophenyl)(2-phenylquinolin-3-yl)metha-
none (3). a. A solution of 0.006 g (20 mol %) of
potassium hydroxide in 0.5 mL of water was added to
a mixture of 0.064 g (0.500 mmol) of quinoline (1) and
0
.126 g (0.500 mmol) of acetylene 2. The mixture was
stirred for 24 h at 55–60°C, water was removed under
reduced pressure, and the residue was subjected to
column chromatography to isolate 0.043 g (24%) of
quinoline 3 as light brown powder, mp 184–186°C
–
1
The expected high reactivity of intermediates A–E
could favor their other transformations, which would
reduce the yield of final product 3.
(from Et O). IR spectrum, ν, cm : 1665 (C=O), 1524
2
1
(NO ). H NMR spectrum, δ, ppm: 7.24 m (3H, m-H,
2
p-H), 7.64 m (1H, 6-H), 7.54 m (2H, o-H), 7.72 m (2H,
Scheme 4.
H
2
N
O
H
2
O
N
O
OH–
N
O
1
Ph
Ar
Ph
Ar
Ph
H
O
Ar
A
B
C
CHO
O
OCH
CHO
O
O
NH
OH–
Ar
Ar
3
+
MeCHO
Ph
Ar
N
Ph
N
Ph
D
E
F
2 6 4
Ar = 4-O NC H .
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 12 2018

2
3
SIMULTANEOUS DOUBLE C /C FUNCTIONALIZATION OF QUINOLINE
1847
2
8
4
′-H, 6′-H), 7.86 m (1H, 7-H), 7.94 m (1H, 5-H),
.05 m (2H, 3′-H, 5′-H), 8.25 m (1H, 8-H), 8.44 s (1H,
tography was performed on Silica gel 60 (0.060–
0.200 mm) using chloroform–benzene–ethanol
(20:4:1) as eluent.
1
3
4a
-H). C NMR spectrum, δ , ppm: 126.0 (C ), 127.8
C
3′
6
5
5′
m
(
C ), 128.4 (C ), 123.5 (C , C ), 128.8 (C ), 129.4
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 18-03-00762) using the equipment of the Baikal
Joint Analytical Center (Siberian Branch, Russian
Academy of Sciences).
p
o
8
2′
6′
(
C ), 129.5 (C ), 129.9 (C ), 130.6 (C , C ), 131.9
7
3
4
i
1′
(
C ), 131.8 (C ), 138.6 (C ), 139.6 (C ), 141.9 (C ),
8
a
4′
2
1
48.8 (C ), 150.1 (C ), 157.1 (C ), 195.6 (C=O).
Found, %: C 74.87; H 3.93; N 7.52. C H N O .
Calculated, %: C 74.57; H 3.98; N 7.91.
2
2
14
2
3
b. A solution of 0.006 g (20 mol %) of potassium
hydroxide in 0.5 mL of water was added to a solution
of 0.064 g (0.500 mmol) of quinoline (1) and 0.126 g
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13
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o
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C
m
2′
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i
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1
′
4′
3
1
1
1
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8
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 12 2018