An atom economical method for the direct synthesis of quinoline derivatives from substituted o-nitrotoluenes

Article abstract of DOI:10.1039/c4cc09358e

A highly efficient one-pot procedure for the preparation of substituted quinolines from substituted o-nitrotoluenes with electron-withdrawing groups and olefins (acrylic esters and acrylonitriles) using a cesium catalyst has been developed. A plausible [2+4] cycloaddition mechanism is proposed. This method uses nitroaromatic compounds as the starting materials to give quinoline derivatives in good to high yields under mild conditions with no transition metal catalysis. It provides an atom economical pathway for the synthesis of quinoline derivatives which could be used in industrial processes.

Full text of DOI:10.1039/c4cc09358e

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An Atom Economical Method for Quinoline
Derivatives Direct from Substituted o-Nitrotoluenes
Cite this: DOI: 10.1039/x0xx00000x
Guiyan Liu,*a Maocong Yi,b Lu Liu,b Jingjing Wangb and Jianhui Wang*b
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
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temperatures under strongly acidic conditions.10a,16,17 The use of
A highly efficient one-pot procedure for the preparation of
substituted quinolines from substituted o-nitrotoluenes with
electron-withdrawing groups and olefins (acrylic esters and
acrylonitriles) using a cesium catalyst has been developed. A
plausible [2 + 4] cycloaddition mechanism is proposed. This
method uses nitroaromatic compounds as the starting
materials to give quinoline derivatives in good to high yields
under mild conditions and with no transition metal catalysis.
It provides an atom economical pathway for the synthesis of
quinoline derivatives which could be used in industrial
processes.
palladium,18 rhodium,19 ruthenium,20 copper21 and gold22 metalꢀ
catalyzed approaches have significantly lessened the harsh
conditions. However, these methods are still limited because
they lack generality and have limited functionalꢀgroup
tolerance.
Quinoline and its derivatives are key skeletons in numerous
organic compounds, many of which have important
applications.1 The quinoline unit is frequently used as a core
structure for the design of modern pharmaceuticals and related
compounds such as antibacterials,2,3 anticancer agents,4
antifungals,5,6 antimalarials,7,8 and antischizophrenia drugs.9
Functionalized quinolines are also important photoꢀsensitive
materials and have been applied to analyses,10 the dye
industry,11 organic electroluminescent devices,12 and optical
recording media.13 Owing to the vast array of uses, there
continues to be an intense focus on the synthesis of substituted
quinolines.
Quinoline and its derivatives can be formed in three ways: a)
the formation of the benzene and pyridine rings at the same
time;14 b) the cyclization of the benzene ring after the formation
of the pyridine ring;15 and c) the cyclization of the pyridine ring
after the formation of the benzene ring. There are only a few
examples of the construction of quinoline and its derivatives by
methods a and b. Only method c is commonly used to produce
quinoline and its derivatives.
Fig. 1 Comparison of the traditional and this work’s synthetic protocols for
quinoline derivatives. Important frameworks associated with the traditional
methods (a), model reaction for this work’s method (b). R1 = -ether, -NO2, -
COOEt, -CN, -CF3 or 4-((3-nitrophenyl)sulfonyl)-; R2 = -COOEt or , -CN.
Up until now, both the traditional procedures and the newly
developed metal catalysis methods began with aniline or
substituted aniline which originates from nitrobenzene
compounds. If a direct synthetic method that started with
aromatic nitro compounds could be established for the
construction of quinoline derivatives, it would be more efficient
since the synthetic pathway would be significantly shortened
and the costs would be reduced. This is in line with the modern
concept of atom economy.23 So,
a simple and direct
transformation of nitrobenzene or substituted nitrobenzene to
quinoline and its derivatives is very desirable.
Herein,
a oneꢀpot, highly efficient method for the
construction of substituted quinolines from substituted
o
ꢀ
nitrotoluene derivatives and acrylic esters or acrylonitriles
using a cesium catalyst is reported (Fig. 1, b). This new strategy
results in quinoline derivates with electron withdrawing groups
in an atom economical way. Achieving these compounds by
traditional routes requires complex synthetic methods. Thus,
this could be an attractive procedure for quinoline derivates that
could be used in industrial processes.
Method c has been used to develop many synthetic methods
to prepare quinolines derivatives with different properties.1c
Generally, there are four types of intermediates that are
associated with the c method (Fig. 1, a). Usually, these
intermediates are generated from functionalized anilines which
are synthesized from nitrobenzene or substituted nitrobenzenes
and α,βꢀunsaturated carbonyl compounds at elevated
Our investigation started with the reaction of 2,4–
dinitrotoluene (1a) and ethyl acrylate (2a) with 2 equiv of 1,4ꢀ
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DOI: 10.1039/C4CC09358E
diazabicyclo[2.2.2]octane (DABCO) or NEt3 as a base in THF at carboxylate (3n) in 79% yield. Substrates 1o
65 oC (Table 1, entries 1 and 2). A low yield of ethyl 7ꢀ quinoline derivatives 3o
3p, and 3q in yields of 63%, 67%, and
nitroquinolineꢀ2ꢀcarboxylate (3a) (less than 10%) was obtained. he 68% respectively. If methyl and nitro groups were situated on
, 1p, and 1q, gave
,
T
1,4ꢀMichael type addition product, ethyl 4ꢀ(2,4ꢀdinitrophenyl)butꢀ3ꢀ the electron deficient aromatic ring, for example, 4ꢀmethylꢀ3ꢀ
enoate, was not observed. The reaction did not proceed without a nitroquinoline (1r), the reaction with 2a proceeded smoothly to
base present. When the base was changed to an inorganic base, such give the desired product (3r) in 91% yield. However, substrates
as Na2CO3, K3PO4, K2CO3 or KOH, the product yields of 3a without an electronꢀwithdrawing group on the arene ring did
increased to 32%, 38%, 51%, and 81% respectively after 12 h of not react with 2a to give the desired quinoline derivatives even
reaction (entries 3ꢀ6). The highest yield of 3a (83%) was obtained with a stronger base such as tꢀBuOK. These results clearly
when Cs2CO3 was used as the base (entry 8). Solvent and the demonstrate the importance of an electronꢀwithdrawing
amount of base screening showed that the optimal result could be substituent in forming the transition state that finally leads to
obtained with Cs2CO3, 1a, and 2a in a mole ratio of 2:1:3 in THF at the quinoline ring.
65 oC.
The substituted oꢀnitrotoluenes, 1a
,
1b
, 1d, 1e, and 1k-1r
also reacted with acrylonitrile 2b
(
) to give substituted
Table 1 Optimization of the conditions for the reaction of 2,4–dinitrotoluene
(1a) with acrylic ethyl ester (2a).
quinolineꢀ2ꢀcarbonitrile products (4a (66%), 4b (66%), 4d
(66%), 4e (66%), 4k-4r (65%ꢀ93%) under similar reaction
conditions (Table 3). The isolated yields of these reactions are
comparable with those for the reactions with 2a
.
The formation of unexpected quinoline derivatives in the
reaction between the substituted oꢀnitrotoluenes and olefins
inspired us perform more experiments to uncover the reaction
mechanism. It is known that oꢀnitrotoluene (1a
transforms to its nitronate isomer (
) (Scheme 1)24 and that
when Cs2CO3 is present in the reaction system, this isomer can
be further stabilized by forming a Cs salt ( ). Initially, we
suspected a twoꢀstep mechanism where a 1,4ꢀMichael type
addition of the methylene anion to the olefin produced 14 as
) easily
7
8
8
an important intermediate and then the carbanion attacked the
nitrogen cation of the nitro group. However, the attempt to trap
the proposed key intermediate 14 by a reaction of 1a with
acrylic ethyl ester failed.
Instead 1a quickly converted to 3a in high yield and no key
intermediates were observed during or after the reaction by
either NMR or TLC, indicating that the key intermediate 14
may only form in very low concentrations and that it quickly
converts to product 3a. To further demonstrate the possibility of
a twoꢀstep mechanism, compound 14 was prepared by crossꢀ
coupling 1ꢀbromoꢀ2,4ꢀdinitrobenzene with (4ꢀethoxyꢀ4ꢀ
oxobutyl)zinc(II) bromide using a palladium catalyst (see the
Supporting Information). Then, 14 was reacted with 2 equiv of
Cs2CO3 in THF. However, the desired ethyl 7ꢀnitroquinolineꢀ2ꢀ
carboxylate (3a) was not observed when the reaction was
conducted at 65 oC even for 24 h. When a stronger base such as
a Molar ratio of base:1a:2a. b Isolated yields.
Next, the scope and limitations of this reaction for the
synthesis of quinoline derivatives were examined using the
optimized reaction conditions and the results are shown in
Table 2. A variety of substituted
withdrawing groups proved to be very efficient substrates under
the optimized reaction conditions. When 2a was reacted with
oꢀnitrotoluenes with electronꢀ
tꢀBuOK was used in combination with Cs2CO3, the reaction
gave a complex product mixture and 3a could not be isolated
from the reaction system. Based on these results, the hypothesis
of a twoꢀstep mechanism was eliminated.
o
ꢀ
nitrotoluenes with substituents such as ꢀNO2 (1a), ꢀCN (1b), ꢀ
COOEt (1c) or (3ꢀNO2ꢀPh)SO2ꢀ (1d), at the 4ꢀposition, the
desired 6ꢀsubstitutedꢀquinolineꢀ2ꢀcarboxylic acid ethyl esters
3a, 3b, 3c, and 3d were obtained in isolated yields of 83%,
74%, 82%, and 81%, respectively.
A ꢀNO2 group at the 6ꢀposition of
So, a oneꢀstep mechanism involving a [2 + 4] cycloaddition
of nitronate
cycloaddition of nitronate
olefin gives cyclic compound
in then gives 10 as an intermediate which contains two
8
to olefin
2
is proposed (Scheme 1). First, a [2 + 4]
, an analogue of 1,3ꢀbutadiene, to
. A hydrogen transfer reaction
8
2
9
o
ꢀnitrotoluene (1e) also
9
reacted with 2a but a yield of only 66% of the desired product
3e was obtained. When a ꢀNO2 group was at the 6ꢀposition and
a –COOEt or a –CON(CH3)2 group was at the 4ꢀposition, the
desired products 3f (86% yield) and 3g (73% yield) were
produced. When oꢀnitrotoluene contained ꢀNO2 at the 4ꢀ
position and another ꢀNO2 group at the 6ꢀposition, or another
group (such as –CON(CH3)2, –COOEt, ꢀCF3 or –CH3) at the 5ꢀ
postiton, the reaction still progressed smoothly and gave the
desired products in good yield (3h-80%, 3i-81%, 3j-80%, 3k-
79%, 3l-82%, and 3m-88%).
hydroxyl groups connected to the same atom. Dehydration of
10 gives nitrone analogue 11. Intermediate 11 has nitrogen
oxide structure 12 as its resonance form. A proton transfer in 12
then gives 13 as an intermediate. The allylic proton is then
attacked by the base and after the release of a water molecule,
the quinoline derivative is formed as the final product.
In conclusion, a new strategy for the direct synthesis of
quinoline derivatives from substituted oꢀnitrotoluene was
developed based on a Cs2CO3 catalyzed [2 + 4] cycloaddition
protocol. This is a oneꢀstep procedure to produce quinolone
building blocks under mild reaction conditions using oꢀ
nitrotoluene as the starting materials. Water molecules are the
A substitution on the methyl group of
influence on the reaction with 2a; thus, 2,4ꢀdinitroethylbenzene
1n) reacted with 2a to give ethyl 4ꢀmethylꢀ7ꢀnitroquinolineꢀ2ꢀ
1 had almost no
(
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Table 2 Synthesis of quinoline derivates via the reaction of substituted oꢀnitrotoluenes with acrylic ethyl ester.a,b
aConditions: 1a (1.0 mmol), 2a (3.0 mmol), CsCO3(2.0 mmol), THF (5.0 mL). bIsolated Yield.
Table 3 Synthesis of quinoline derivates via the reaction of substituted oꢀnitrotoluenes with acrylonitrile.a,b
aConditions: 1a (1.0 mmol), 2b (3.0 mmol), CsCO3(2.0 mmol), THF (5.0 mL). bIsolated Yield.
Scheme 1 The proposed reaction mechanism for the synthesis of quinoline derivates via the reaction of substituted o-nitrotoluenes with an olefin.
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DOI: 10.1039/C4CC09358E
only fragments lost in these reactions, so this represents an
atom economical process for the construction of functionalized
quinoline derivatives. The unusual 1,4ꢀcycloaddition of
nitronate to an olefin provide an opportunity to generate ring
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derivatives under mild reaction conditions. This method might
be extended to ꢀnitrotoluene or ꢀnitrotoluenes with electron
oꢀnitrotoluene
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