Effective water mediated green synthesis of polysubstituted quinolines without energy expenditure

Article abstract of DOI:10.1007/s00706-016-1826-3

Abstract: This study explores a green methodology for the synthesis of polysubstituted quinolines through Friedl?nder annulation using water as a solvent. To evaluate the viability of this methodology, results obtained were compared with methods involving

Full text of DOI:10.1007/s00706-016-1826-3

Monatsh Chem
DOI 10.1007/s00706-016-1826-3
ORIGINAL PAPER
Effective water mediated green synthesis of polysubstituted
quinolines without energy expenditure
P. Gopi1 S. Sarveswari1
•
Received: 11 May 2016 / Accepted: 26 July 2016
Ó Springer-Verlag Wien 2016
Abstract This study explores a green methodology for the
¨
synthesis of polysubstituted quinolines through Friedlander
Introduction
annulation using water as a solvent. To evaluate the via-
bility of this methodology, results obtained were compared
with methods involving the usage of energy, such as
mechanical stirring, heating, microwave irradiation, and
solvent free heating reaction. To demonstrate the efficiency
and consistency of this method, a bulk batch reaction has
been performed using this protocol and many quinoline
derivatives have been synthesised and characterised by 1H,
13C NMR, melting range, and HR-MS.
Quinoline derivatives have wide range of applications from
medicine [1] to materials [2, 3]. Most of the polysubstituted
¨
quinolines were synthesised by Friedlander annulation. A
large number of modifications have been carried out in the
¨
Friedlander synthesis [4], though the modifications and
developments are keep going in the same field, every
seconds are peeling out old skin and getting new of its own.
¨
After the discovery of Friedlander quinoline synthesis,
numerous strategies have been developed to synthesise
quinoline by changing starting precursors, catalysts, reac-
tion conditions, using different energy sources
(conventional heating [5] and microwave irradiation [6]).
Graphical abstract
¨
Generally, Friedlander reactions were performed either
in the presence of base as a catalyst or high temperature
reflux in solvent in the absence of catalyst. Initially,
¨
Kempter and co-workers modified the Friedlander annu-
lation using hydrochlorides of o-aminoarylketones and they
reported that acids are more favourable catalysts than the
bases [4]. Subsequently, scientists were invaded to use acid
catalyst for the synthesis of quinoline. In recent years,
¨
many literatures can be found on simplifying Friedlander
¨
Keywords Microwave Á Friedlander annulation Á
annulation using Lewis acids [7, 8], metal salts [9–12],
metal nano particles [13, 14], Lewis acid surfactant com-
bined catalyst [15], iodine [16], chitosan-SO3H [17],
propylphosphonic anhydride (T3P) [18, 19], hydrochloric
acid (HCl) [20], sulfuric acid (H2SO4) [21], trifluoroacetic
acid (TFA) [22], p-toluenesulfonic acid [23]. Unfortu-
nately, these techniques suffer from harsh reaction
conditions, unfavourable for large scale, expensive catalyst
usage, inadequate catalyst reusability, power consumption,
hazardous reagents, organic solvents, and waste disposal.
It is essential to develop a method for the synthesis of
polysubstituted quinolines in bulk scale. When considering
Green chemistry
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-016-1826-3) contains supplementary
material, which is available to authorized users.
& S. Sarveswari
sarveswari@gmail.com
1
Department of Chemistry, School of Advanced Sciences, VIT
University, Vellore 632014, India
123

P. Gopi, S. Sarveswari
the kilogram level of transformation, the process should be
inexpensive, reproducible, lesser power conceptive, good
yield and less wastage productive, less hazardous, benign,
involving mild reaction condition and benign solvent usage
[24], but there is no perfect green solvent for all type of
reactions [25]. Water is an innocuous solvent [26], and
hence mostly used in green synthesis [27]. The present
the exact ratio of starting intermediate, we performed reac-
tion in water with different proportion of reactants. When we
increased the amount of diketone from 1.5 to 2.0 equivalents
with fixed proportion of hydrochloric acid there was no
change in conversion then, we increased the hydrochloric
acid proportion from 1.0 to 3.0 equivalents and observed that
the yield was increased to 45 % but reaction was not com-
pleted. When the amount of diketone was increased to 2.2
equivalents then the reaction was found to be completed.
Finally, 1:2.2:3 (2-amino-5-chlorobenzophenone, acety-
lacetone, hydrochloric acid) equivalent ratio gave the
maximum yield with completion of reaction. Results were
furnished in Table 1.
¨
work made an attempt to simplify the Friedlander annula-
tion and established a methodology without any energy
expenditure in the presence of aqueous hydrochloric acid in
water medium at room temperature. We have chosen green
solvents (water) and have carried out the experiments and
evaluated the efficiency of the solvent towards synthesis of
¨
quinolines by Friedlander annulations without energy
Subsequently, the optimised reaction conditions was
extended to various electron donating and electron releas-
ing group substituted o-aminoarylketone, aromatic
diketone, aliphatic diketone, chlorodiketone, aliphatic
ketoester, aliphatic cyclic ketone, cyclic diketone,
aryldiketone, N-methylpiperidone, N,N-dimethylacetamide
to get the corresponding quinoline derivative and to prove
the generality of the reaction.
expenditure. The newly developed procedure has been
applied to prepare various reported polysubstituted quino-
line derivatives and extended to unreported derivatives as
well.
Results and discussion
The lesser yield may be attributed with the heterogeneity
of reaction mixture. Due to this heterogeneity, water
mediated reactions required additionally one more equiva-
lent diketone. The additional equivalent of a diketone may
complete the reaction by increasing the availability of
diketone and the proximity of starting material. The water
mediated reaction has not resulted in the formation of few
compounds (5, 6, 8, 9, 10, 24). It might be due to inadequate
solubility of solid diketones. These reactions to afford
compounds 5, 6, 8, 9, 10, 24 were not found to proceed in
different proportion of water and methanol mixture (50:50,
25:75) also. Though water mediated process requires an
additional equivalent of starting material, it can be regarded
as a benign process using green solvent without the need of
distillation. The work up was done simply by adding the
Initially, we carried out the synthesis of quinoline deriva-
tives with trifluoroacetic acid, sulfuric acid, and
hydrochloric acid as a catalyst in water at room tempera-
ture (RT) without shaking, stirring, heating, microwave
irradiation, or sonication. Trifluoroacetic acid and sulfuric
acid have shown comparable results with hydrochloric
acid, but trifluoroacetic acid and sulfuric acid are corrosive
and are not benign. Hence, we specifically focused on
hydrochloric acid and used it as a catalyst.
We performed reactions at room temperature by treating
2-amino-5-chlorobenzophenone, acetylacetone, hydrochlo-
ric acid in water with different ratio of precursors. In water,
2-amino-5-chlorobenzophenone was not consumed com-
pletely in absence of hydrochloric acid in 1:1:1 ratio. To fix
Table 1 Optimisation of reaction conditions
Entry
HCl/eq.
Diketone/eq.
Solvent
Time/h
Yield/%
1
2
3
4
5
6
7
8
9
–
1.0
1.0
1.5
2.0
2.0
2.0
2.0
2.0
2.2
MeOH
Water
Water
Water
Water
Water
Water
Water
Water
24
24
24
24
24
24
24
24
16
No product
Traces
26b
29b
52b
67b
73b
75b
90a
1.0
1.0
1.0
1.5
2.0
2.5
3.0
3.0
Reaction conditions: HCl and diketone have been taken with respect to 1 eq of o-aminoketone
a
o-Aminoketone 100 % conversion
b
o-Aminoketone not 100 % conversion
123

Effective water mediated green synthesis of polysubstituted quinolines without energy…
Table 2 Yield and reaction
time of water mediated
quinoline synthesis in the
presence of HCl at RT
/
o-Aminoaryl-
ketone
Time
h
M.p./°C
(Lit.)
Entry
1
Diketone
Product
Yield
90
221–223
(151–154
[21])
16
19
1
98–100
(102–105
[21])
2
3
78
86
2
225-227
(225-227
[6])
5
3
228–232
(185–189
[22])
4
14
85
4
5
6
7
24
24
–
–
5
6
5
days
73
140–143
7
8
9
24
–
–
8
106–108
(105–106
[9])
24
9
solution of NaHCO3 (pH around 9–10) into the reaction
mixture. After the addition of NaHCO3 solution, the solid
obtained was filtered and washed with water to afford the
product. It may applicable for cost effective preparation of
some quinoline derivatives. Yield and reaction time were
furnished in Table 2.
123

P. Gopi, S. Sarveswari
Table 2 continued
o-Aminoaryl-
Time/
h
M.p./°C
(Lit.)
Entry
10
Diketone
Product
Yield
63
ketone
24
14
222–225
10
122–126
(140–142
[20])
11
79
11
120–122
(120–121
[20])
12
13
16
6
81
84
12
168–171
(172–174
[20])
13
216–220
(170–172
[20])
14
5
82
14
15
16
16
14
79
80
129–131
102–106
15
16
17
12
24
83
–
180–183
17
18
19
18
170–176
(168–170
[9])
19
84
19
To prove the nonenergy expenditure nature of this pro-
cess, we have done same experiments under different
external force like mechanical stirring, heating, microwave
irradiation, and solvent free heating condition then com-
pared the results with non-energy expenditure method
(Fig. 1). When we carried out reaction under stirring with
123

Effective water mediated green synthesis of polysubstituted quinolines without energy…
Table 2 continued
o-Aminoaryl-
Time/
h
M.p./°C
(Lit.)
Entry
Diketone
Product
Yield
84
ketone
109–110
(96–100
[9])
20
19
20
140–142
21
22
23
24
25
5
5
89
84
82
–
(138 [28])
21
22
153–154
(158 [14])
11
days
98-100
23
24
24
18
68
232–236
25
26
26
27
12
14
74
78
Oil
155–160
27
28
16
67
158–161
28
different RPM (rotation per minute) no change in the
reaction time and yield was observed in both solvents.
When reaction mass was heterogeneous, reactants will be
static to make collision it requires external force like stir-
ring or shaking. In the homogenous mixture, due to
molecular rotations and vibrations, collision will take place
effortlessly without external force. This may be the reason
why there was no difference in yield and reaction time in
the processes with and without the energy expenditure.
Same reactions were performed under conventional heating
and microwave irradiation. Conventional heating (90 °C)
acquired 5 h. Under microwave irradiation (340 W) reac-
tion was completed within 10 min.
Isolation of product was simply by filtration and wash-
ing with NaHCO3 and water. No column chromatography
was used for the product purification. Compound 26 is a
liquid in nature; we used diethyl ether for extraction. To
exhibit the consistency of the process, we performed 50 g
123

P. Gopi, S. Sarveswari
Without energy
Machnical stirring
Temperature
comparing with the processes involving energy expendi-
ture, such as stirring, heating, microwave irradiation, and
solvent free heating reaction. Using these protocols suc-
cessfully, 22 compounds were synthesised and
characterised.
100
80
60
Yield/%
Microwave
irradiation
40
20
0
Experimental
Solvent renewal
experiment
Traces
All chemicals and regents were used for experiments which
are commercially available and used without further
purification. Reactions were monitored by TLC. NMR
spectra were recorded on Bruker Avance 400 MHz spec-
trometer, with TMS as an internal standard. Chemical shift
values were expressed in parts per million (ppm). Abbre-
viations are as follows: s, singlet; d, doublet; t, triplet; m,
multiplet; bs broad singlet. The melting range of synthe-
sised compounds was determined by Elchem
Microprocessor based DT apparatus using an open capil-
lary tubes and are calibrated with benzoic acid.
Solvent free
heating
Reaction conditions
Fig. 1 Comparison of non-energy expenditure process with energy
required process
(21.6 mmol 2-amino-5-chlorobenzophenone, 47.52 mmol
of acetylacetone, 64.8 cm3 of hydrochloric acid) batch size
reaction in a 1 dm3 beaker without agitation kept the
reaction mixture for appropriate time (Scheme 1). Reaction
mixture was slowly added into a 200 cm3 of 20 % sodium
bicarbonate solution, solid obtained was filtered and
washed with 200 cm3 water and then with 33 cm3 of die-
thyl ether.
General synthesis of polysubstituted quinolines
HCl (10 N, 3.0 cm3) was added to 10 mmol of
aminoarylketone and 15 cm3 of distilled water followed by
22 mmol of diketone; the reaction mixture was allowed to
be placed at room temperature for appropriate time without
agitation. The completion of reaction was confirmed by
TLC. Reaction mixture was basified with 10 cm3 20 %
NaHCO3 and the solid was filtered and washed with
20 cm3 water followed by 1.5 cm3 diethyl ether, then dried
over air.
We performed experiments using 1 eq of o-aminoke-
tone, 6 eq of diketone in solvent free heating condition
(120 °C). Reactions were not completed and only a few
combinations of reactants shown the traces product for-
mation in TLC (1, 2, 19, 20).
Conclusions
This work explored green methodology for the synthesis of
quinoline derivatives. The advantage of this method is cost
effectiveness and benign process since it involves water as
a solvent and no energy expenditure. Also, this work was a
successful method for the preparation of polysubstituted
quinolines in large scale to confirm the efficiency of the
method. Pure compounds were obtained without the use of
noxious organic solvents (no column chromatography was
performed). This green methodology was evaluated by
8-Chloro-2-methyl-10-phenyl-1,2,3,4-tetrahy-
drobenzo[b][1,6]naphthyridine (7, C19H17ClN2)
Pale yellow crystal; m.p.: 140–143 °C; 1H NMR
(400 MHz, CDCl3): d = 2.32 (s, 3H), 2.78 (t, 2H), 3.32
(t, 2H), 7.23–7.14 (m, 3H), 7.50–715 (m, 4H), 7.88 (d,
J = 9.2 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3):
d = 33.8, 46.1, 52.8, 56.7, 124.6, 126.8, 127.1, 128.4,
128.8, 128.9, 129.7, 130.1, 131.5, 135.2, 144.2, 145.1,
156.3 ppm.
Scheme 1
O
O
O
O
l
C
l
C
Ph
NH2
H l RT
C
,
+
N
50
26
g
g
.
58 7 92
%
)
g
(
123

Effective water mediated green synthesis of polysubstituted quinolines without energy…
6-Chloro-N,N,2-trimethyl-4-phenylquinoline-3-carbox-
amide (10, C19H17ClN2O)
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White crystal; m.p.: 222–225 °C; 1H NMR (400 MHz,
CDCl3): d = 2.58 (s, 3H), 2.85 (s, 3H), 3.15 (s, 3H), 7.38
(m, 1H), 7.65–7.56 (m, 4H), 7.77 (d, J = 2.4 Hz, 1H),
7.94–7.91 (m, 1H), 9.04 (d, J = 8.8 Hz, 1H) ppm; 13C
NMR (100 MHz, CDCl3): d = 19.0, 34.4, 37.7, 123.8,
125.9, 127.0, 128.5, 128.6, 129.4, 129.6, 130.9, 131.8,
131.9, 135.0, 136.4, 137.0, 151.5, 154.4, 164.1 ppm.
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Brown crystal; m.p.: 98–100 °C; 1H NMR (400 MHz,
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1
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´
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Acknowledgments We thank to VIT management for providing
research facility, and thanks to VIT-SIF, DST-FIST for providing
NMR facilities to carry out this work.
123