Bioorganopromoted green Friedl?nder synthesis: a versatile new malic acid promoted solvent free approach to multisubstituted quinolines

Article abstract of DOI:10.1039/c6nj03907c

The discovery of a new, malic acid promoted, eco-friendly Friedl?nder approach to varied multisubstituted quinolines is disclosed. To the best of our knowledge, this is the first report on the use of malic acid, classified as one of the 12 biobased hot molecules by the US Department of Energy, as an organopromoter in organic synthesis and includes many benefits like wide substrate scope, solvent free ambient reaction conditions, short reaction times, operational simplicity, cost effectiveness, high atom economy, good to excellent yields, and recylability of the organopromoter, making it a valuable green alternative to the existing methods. The versatility and practicability of the developed method was further established by its successful application towards the targeted synthesis of some important quinoline molecules and successful scale up.

Full text of DOI:10.1039/c6nj03907c

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The role of atropisomers on the photo-reactivity and fatigue of
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Bioorganopromoted Green Friedländer : A versatile new Malic
acid promoted solvent free approach to multisubstituted
quinolines
Received 00th January 20xx,
Accepted 00th January 20xx
Fatima Tufail, a# Mohammad Saquib, a# Swastika Singh, a Jyoti Tiwari, a Mandavi Singh, a Jaya Singh,
b Jagdamba Singh a*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The discovery of a new, malic acid promoted, eco-friendly Friedländer approach to varied multisubstituted quinolines is
disclosed. To the best of our knowledge this is the first report on the use of malic acid, classified as one of the 12 biobased
hot molecules by US Department of Energy, as an organopromoter in organic synthesis and includes many benefits like
wide substrate scope, solvent free ambient reaction conditions, short reaction times, operational simplicity, cost
effectiveness, high atom economy, and good to excellent yields, recylability of the organopromoter, making it a valuable
green alternative to existing methods. The versatility and practicability of the developed method was further established
by its successful application towards the targeted synthesis of few important quinoline molecules and successful scale up.
14,15
the for the synthesis of quinolines are known,3-5,
Friedländer annulation remains by far one of the most popular
and useful methods for the synthesis of quinolines, as
Introduction
Many of the traditional synthetic methodologies have wide
applications but are not in consonance with green chemistry
principles. However with the growing awareness for the need
to prevent harm to the environment, the development of
more environmentally acceptable processes in organic
synthesis have become imperative.1
evidenced by the
O
O
COOMe
O
OMe
N
MeO
MeO
N
O
O
O
N
N
MeO
MeO
N
O
O
N
O
O
N
Anti-cancer13d
Anticancer13e, 13f
OH
13c
Irinotecan
Friedländer,2,3 a two component reaction (2-CR), between an
o-acyl anilines and carbonyl compounds containing an α-
methylene group to obtain polysubstituted quinolines, is one
such important synthetic protocol which was discovered more
than 100 years back, but remains as relevant as before.3-5
Quinoline is an important heterocyclic scaffold with immense
applications in diverse fields ranging from material chemistry6
to medicinal chemistry7-14 (Figure 1). However nowhere its role
is more well defined than in medicinal chemistry.10 The
prominence of quinoline motif in antimalarial drug
development is well documented.11 However in recent years
quinolines have also gained recognition as an important
privileged scaffold for the development of new therapeutics in
other disease areas12 particularly cancer13 and tuberculosis.14
As a consequence the discovery of more efficient and versatile
new routes for the synthesis of quinolines remains of the hot
areas in organic synthesis.15,16 Though a variety of methods for
GI50 = 0.002 µM; MCF-7
IC50= 2.0 µg/mL
Anti-cancer
OMe
N
N
OMe
S
S
COOEt
Cl
Cl
Cl
S
COOEt
MeO
MeO
N
Cl
N
N
N
Br
N
N
N
N
Antitubercular14
Antitubercular14
Anti-protozoal10c
IC50= 0.98µg/mL; T. cr uzi
Anti-inflammatory12b
(DMARD)
MIC= 0.90 µg/mL; MTB
MIC=3.2 mM; MTB
F
O
OH OH
O
H2N
O
OH
CN
NH2
N
OH
N
N
N
OH
Pitavastatin12c
TPQ6d, 6e
O
Antioxidant12a
AAC-26f
HMG-CoA reductase inhibitors
OLEDs fabrication
(Anti-corrosive agent)
EC50=22.7µmol: RSA=78%
O
O
Cl
COOEt
O
N
N
N
N
TPQ
Representative Prototype Molecules
Figure 1. Some important 2,3,4-trisubstituted quinolines and synthesized prototypes
from present work
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large number of recent reports on the Friedländer synthesis of
quinolines. Friedländer annulation remains by far one of the
most popular and useful methods for the synthesis of
quinolines, as evidenced by the large number of recent reports
on the Friedländer synthesis of quinolines.5,18-20
Results and Discussion
In our quest to design an ideal green methodology for the
synthesis of polysubstituted quinolines using the Friedländer
strategy, we decided to explore biobased organic acids as
However, many of these Friedländer based approaches are not
in consonance with the principles of green chemistry in as they
involve the use of toxic catalysts, volatile organic solvents and
harsh reaction conditions.5,18 This has prompted the search
for eco-friendly Friedlander protocols leading to the
development of a number of eco-compatible Friedlander
approaches in recent years.19,20 Though many of these
methods are quite useful, they do suffer from drawbacks like
use of expensive catalysts, high reaction temperature, long
reaction times, operational complexity etc. To better illustrate
this issue we examined two important eco-friendly methods
Table 1. Screening of Organoacids
O
O
O
Organoacid
O
O
+
O
NH2
N
3
1
2
Entry
1
Organoacid (50 mol %)
Citric acid
Time (h)
Yield of 3b (%)c
reported in the literature. One report is that of C. Najera et al
19d
who
used
1,1'-Binaphthalene-2,2'-diamine-derived
4
4.5
4
79
65
prolinamide as organocatalyst. However this organocatalyst is
highly expensive and not available commercially. Also the
reaction time is quite long. Another important paper in this
context is that of G-W. Wang and co-workers20c who reported
the synthesis of polysubstituted quinolines in the presence of
TsOH. However this method uses one equivalent of the
organocatalyst at high temperature (100 °C).This necessitates
the uninterrupted pursuit of better methods which are
greener, more efficient and easier to operate.
2
Malonic acid
Tartaric acid
Benzoic acid
Cinnamic acid
Mandelic acid
Malic acid
3
62
4
8
57
5
8
50
Organocatalysis is one of the fastest growing areas in synthetic
chemistry in the last few years, due to the innate benefits
involved in using small organic molecules of biological origin as
promoters, which are typically non-toxic, insensitive to
moisture and air, cost-effective, easily available, efficient and
selective.21,22 Their potential advantages become all the more
relevant in context of green synthesis since the real benefit of
organopromoters is best realized when used in combination
with green solvents or solvent free conditions.23
6
7
61
7
1.2
8
85
8
Acetic acid
43
9
Oxalic acid
4
82
Organic acids of biological origin could serve as ideal green
replacements24 for mineral acid and metal or non-metal Lewis
acid promoters in organic synthesis. However, surprisingly
they remain largely under-utilized and underexplored.
10
11
12
13
Ascorbic Acid
Succinic Acid
Fumaric Acid
No promoter
8
58
8
49
Malic acid, a C-4 dicarboxylic, α-hydroxy acid, is recognized as
an important bioorganic molecule - listed as one of the 12
biobased hot molecules by US Department of Energy.25-26
However its use in organic synthesis largely remains
8
58
8
Trace
unexplored.
The opening up of new possibilities for
a All reactions were carried out with
1
was found to be 92-95 °C (Reported 93 °C)
(1 mmol) and
2 (1.1 mmol) in neat conditions
17b c
commercial production of malic acid, through microbial under air; b M.P. of compound
Isolated yields
3
;
bioconversion of a cheap and abundant bio-renewable
27
feedstock like glycerol,
could serve as a catalyst for
potential ecofriendly bioorganocatalyst for promoting this
reaction.
exploration of organic acid as a green promoter and building
block in chemical synthesis.
We chose a model Friedländer experiment involving the
reaction of 2-amino benzophenone with ethyl acetoacetate at
50 °C under solvent free conditions, for screening the efficacy
of different organic acids as catalysts (Table 1). It was observed
that among the 13 organic acids screened, malic acid gave the
best result leading to the formation of the desired 2,3,4-
Consequently in our continued pursuit towards the
development of novel green synthetic routes28 for the
construction of biologically important small heterocycles, we
became interested in the design of a new eco-friendly,
efficient and versatile, malic acid catalysed, Friedländer
protocol for the synthesis of multisubstituted quinolines.
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however at higher temperatures a gradual decrease in yield,
was observed (Table 3, entries 7 and 8).
trisubstituted quinoline in 85 % yield in about 1.2 hours (Table
1, entry 7).
This superior performance of malic acid could be rationalised
in terms of its structure. Malic acid being an alpha hydroxy acid
is a stronger acid than normal carboxylic acids. Its chemical
structure facilitates the formation of an internal hydrogen
bond between the hydrogen at the hydroxyl group and one of
the oxygen atoms of the carboxylic group. Due to the
"occupation" of electrons of the carboxylic oxygen in the
hydrogen bonding, the acidic proton is held less strongly, as
the same electrons are used in bonding with hydrogen too. So
the pKa of malic acid is lower than its non-hydroxyl analogs.29
Table 3. Optimization of reaction temperaturea
Entry
1.
Temp (°C)
Time
8 h
Yield of 3 (%)b
Table 2. Optimization of malic acid loadinga
25
40
50
55
60
70
80
100
30
45
70
96
96
96
89
2.
8 h
3.
1.2 h
4.
55 min
55 min
45 min
40 min
5.
Entry
1.
Malic acid (mol%)
Time(h)
Yield of 3 (%)b
6.
5
10
25
50
75
100
8
8
8
2
2
2
30
45
70
96
96
96
7.
2.
8.
35 min
85
a
3.
All reactions were carried out with
conditions under air; b Isolated yields
1
(1 mmol) and
2
(1.1 mmol) in neat
Finally the model experiment was conducted in a variety of
green solvents and in solvent free conditions in order to
identify the best medium for carrying out this reaction (Table
4). From these set of experiments we observed that the
reaction proceeds best in solvent less neat conditions (Table 4,
entry 7).
4.
5.
6.
a
Table 4. Identification of best reaction mediuma
All reactions were carried out with 1 (1 mmol) and 2 (1.1 mmol) in neat
conditions under air; b Isolated yields
Once malic acid had been identified as the best organoacid for
promoting this reaction, we turned our attention towards
optimization of the amount of malic acid needed for obtaining
the best yield of quinoline 3. A series of experiments were
conducted using different quantities of malic acid wherein it
was observed that use of 50 mol% malic acid gave the best
result. While reducing the amount of malic acid led to a big
decrease in yield and increase in reaction time (Table 2, entries
5 and 6) increased promoter loading led to no change in yield
or time (Table 2, entries 1-3).
Yield of 3
Entry
Reaction medium
Time (h)
(%)b
Trace
33
1.
2.
3.
Water
Water/CTAB
Glycerol
8
8
8
Next we investigated the effect of reaction temperature on the
course of the reaction. It was observed that a 5 °C increase in
temperature from 50 °C to 55 °C led to a marked increase in
yield from 85% to 96% (Table 3, entry 4). On further increasing
the temperature till 70 °C no marked change was noticed,
21
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reaction mixture was dissolved in EtOH (2mL) and cold water was
added to it whence the solid product which separated out was
filtered, washed with water and dried to obtain the quinoline
product. The combined filtrate was now dried in vacuo and
washed with a minimum amount of MeTHF to remove any
4.
5.
6.
7.
8.
PEG
Ethanol: Water 4:1
Ethanol
8
8
Trace
67
2
88
Table 6. Substrate scope for cyclic α-methylene compounds a,b
Neat
0.9
4
96
R1
O
X
X
Malic Acid (50 mol%)
55 oC
R1
R2
+
Y
Methanol
82
Y
O
N
8a-j
NH2
1, 4a-b
7a-d
X = CH2 , CO
Y = CH2, C(CH3
a
b
All reactions were carried out with 1 (1 mmol) and 2 (1.1 mmol) under air;
)
2
Isolated yields
With the optimized reaction conditions in hand we set out to
examine the substrate scope of the developed synthetic strategy
by reacting different o-acyl anilines and carbonyl compounds
possessing an active α-methylene group. In all the cases the
reaction proceeded smoothly and the corresponding
polysubstituted quinolines were obtained in good to excellent
yields (Table 5 and 6).
O
O
N
N
N
N
8d,c 83%, 1.1h
8a, 98%, 55 min
8b,
96%, 55 min
8c,c 84%, 1.1h
O
Cl
Cl
Table 5. Substrate scope for acyclic α-methylene compounds a,b
N
N
N
N
8f,c 78%, 1.3h
8e,c 92%, 1.1h
8g, 94%, 1.1 h
8h, 90%, 1.1 h
O
O
R1
O
O
R3
R2
Malic Acid (50 mol%)
55 o
R1
R4
R2
N
+
R3
2, 5a-d
N
NH2
N
6a-jb
C
8i, 80%, 1.3h
8j, 79, 1.2h
1, 4a-b
aAll reactions were carried out with the respective o-acyl aniline 1, 4a or 4b (1
mmol) and respective α-methylene ketone 2 or 5a-d (1.1 mmol) in neat conditions
under air; bAll the synthesized quinolines (8a-j) are known in literature; Relevant
literature references as well as melting points (for all solid compounds) are
provided in Table S1 in ESI; cA few drops of ethanol was added to obtain the
reaction mixture in form of a paste as both the starting materials were solid.
O
O
O
N
N
N
N
NO2
6d,c,d 72%, 4.5h
6a,
6c,c,d
76%, 4.5h
95%, 0.9h
6b, 90%, 0.9h
O
O
O
O
Cl
O
Cl
Cl
O
O
N
N
96
N
N
94
89
1h, 94%, 1h
6g,
6e, 90%, 1.2h
87%, 1.2 h
71
6f, 91%, 1.2h
100
50
0
O
O
O
N
N
6i, 93%, 1h
6j, 90%, 1h
1st cycle
2nd cycle
3rd cycle
4th cycle
aAll reactions were carried out with the respective o-acyl aniline 1, 4a or 4b (1
mmol) and respective α-methylene ketone 2 or 5a-d (1.1 mmol) in neat conditions
under air; bAll the synthesized quinolines (6a-j) are known in literature; Relevant
literature references as well as melting points (for all solid compounds) are
provided in Table S1 in ESI; cA few drops of ethanol was added to obtain the
reaction mixture in form of a paste as both the starting materials were solid;
dReaction temperature 70 °C
CYCLE
Figure 2. Recyclability of Malic acid
trace of residual reagents/product and the pure recycled malic
acid so obtained was used for the next cycle. The recycled
promoter could be reused multiple times with comparable
efficiency without any further treatment. The recyclability of
the promoter offsets the perceived disadvantage of the high
catalyst loading needed for this reaction (Figure 2).
The synthetic strategy worked equally well with both acyclic
and cyclic α-methylene compounds (Table 5 and Table 6
respectively) while in the case of o-acyl anilines, use of 2-
amino benzophenones generally led to higher yields as
compared to 2-amino acetophenones (Table 5 and 6).
In order to test the versatility and robustness of the developed
Friedlander protocol, we applied it for the synthesis of a few
important quinoline molecules (Scheme 1).
Next, we examined the possibility of recovery and recyclability
of malic acid using the model reaction, under the optimized
reaction conditions. Upon completion of the reaction, the
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6d,
For this purpose we selected 2,3,4-Triphenyl Quinoline (TPQ
6e
)
and cheap, promising bioorganic molecule as a catalyst in
10, an important ligand used in synthesis of OLEDs, organic synthesis. Use of solvent free mild reaction conditions,
analogue13e,13f,30
12 and ease of operation and workup, high atom economy, wide
]quinolones13d 14 and 15 which are medicinally substrate tolerance, good to excellent yields and recyclability
important molecules (Scheme 1). All the target molecules were of the promoter are the other important hallmarks of the
azapodophyllotoxin
indeno[2,1
b
synthesized successfully in good to excellent yields and short
reported method. The successful application of the present
method
R1
R1
OH
O
HOOC
R1
O
HOOC
OH
N
H
N
O
H
H
NH2
O
R2
O
HO
R3
HO
R2
O
H
R3
OOC
O
H
R2
O
R3
O
O
COOH
O
H
R1
R1
O
H
COOH
OH
O
R1
OH
OH
R3
H
Isomerization
R2
R2
R3
N
H
N
R2
N
H
R3
R1
N
R1
R2
R3
R2
R3
Scheme 1. Targeted synthesis of TPQ 10, azapodophyllotoxin analogue 12 and
indeno[2,1b]quinolines 14 and 15
N
H
OH
O
HOOC
reaction times. However marginally higher temperatures and
higher promoter loading was required in these cases.
We also performed the model reaction on a multigram scale in
order to ascertain the practicality of the develop methodology
Scheme 3. Plausible mechanism
(Scheme 2). 2-amino benzophenone
1 (10 mmol, 1.972 g) was
reacted with ethyl acetoacetate 2 (11 mmol, 1.403 ml), leading
towards the targeted synthesis of selected important quinoline
molecules and its scale up to multi-gram scale further serve to
make it a valuable green alternative to existing methods.
Moreover the present work also highlights the latent
possibilities of using hitherto unexplored biobased organic
to which was obtained in 94% yield in about 1.3h. All the
reactions including the scale up reaction were carried out
using a common laboratory glasswares under air which
demonstrates the operational ease of this method.
acids as alternative green promoters in organic synthesis
.
Experimental Section
General remarks
All chemicals were reagent grade and purchased from Aldrich,
Alfa Aesar, Merck, Spectrochem and Qualigens and were used
without further purification. The reactions were monitored
using pre-coated Aluminium TLC plates of silica gel G/UV-254
of 0.25 mm thickness (Merck 60 F-254). Column
chromatography was performed using silica gel (60-120) and
(100-200). NMR spectra were recorded on a Bruker Avance-II
400FT spectrometer at 400 MHz (1H) and 100 MHz (13C) in
DMSO or CDCl3 using TMS as an internal reference. Mass
spectra (ESIMS) were obtained on a Waters UPLC-TQD mass
spectrometer. IR spectra were recorded on a Thermo Scientific
Nicolet iS5 FT-IR spectrometer.Elemental analyses were
carried out in a Thermo Scientific (FLASH 2000) CHN Elemental
Analyser. Melting points were determined by open glass
capillary method and were uncorrected.
Scheme 2. Multigram synthesis of quinoline 3
A tentative mechanism for the synthesis of quinolines by the
reaction of o-acyl anilines and α-methylene compounds using
this method is depicted below.
Conclusions
In conclusion we have disclosed a new and efficient malic acid
promoted, green Friedländer approach to diverse
multisubstituted quinolines. To the best of our knowledge this
is the first report on the use of malic acid - an easily available
General Experimental Procedureabc
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o
-acyl anilines (1 6. (a) G. Sarada, J. Yoon, W. Cho, M. Cho, D. W. Cho, S. O. Kang,
, 113-120; (b)
mmol), α-methylene ketone (1.1 mmol) and malic acid (0.5 Y. Nam, J. Y. Li, S. Jin, J. Mater. Chem. C, 2016,
4
mmol) and the resulting mixture was stirred at 55 °C under T. Guo, W. Zhing, A. Zhang, J. Zou, L. Ying, W. Yang, J. Peng,
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control), the reaction mixture was dissolved in EtOH (2mL) and Lai, Q. Su, W. Huang, X. Liu, Chem. Soc. Rev., 2014, 43, 3259–
cold water was added to it whence the solid product which 3302; (d) S. J. Lee, J. S. Park, M. Song, I. A. Shin, Y. I. Kim, J. W.
separated out was filtered, washed with water and dried. The Lee, J. W. Kang, Y. S. Gal, S. Kang, J. Y. Lee, S. H. Jung, H. S. Kim,
crude product was then recrystallized from a mixture of Et2O/ M. Y. Chae and S. H. Jin, Adv. Funct. Mater., 2009, 19, 2205–
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was dissolved in EtOAc and washed with water. The EtOAc 8. A. Marella, O. P. Tanwar, R. Saha, M. R. Ali, S. Srivastava, M.
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Acknowledgements
The authors are thankful to SAIF, PU, Chandigarh and SAIF,
CDRI, Lucknow for spectral data. The authors also
acknowledge the financial support from UGC, New Delhi in
form of a major research project (Project No. 42-263/2013
(SR)), fellowships for Fatima Tufail, Swastika Singh and
Mandavi Singh and a D.S. Kothari Postdoctoral Fellowship for
Dr. Mohammad Saquib (Award No. F.4-2/2006 (BSR)/13-
1030/2013(BSR). Jyoti Tiwari thanks CSIR, New Delhi for Junior
Research Fellowship.
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An efficient new method for the green synthesis of a variety of polysubstituted quinolines using
the Friedländer approach is reported using malic acid as a catalyst in organic synthesis for the
first time.