Toward the synthesis of 6-hydroxyquinoline starting from glycerol via improved microwave-assisted modified Skraup reaction

Article abstract of DOI:10.1016/j.catcom.2013.07.029

An efficient and modified Skraup reaction and Bamberger rearrangement in neat water were developed using nitrobenzene and an inexpensive, abundant and environmentally-friendly glycerol under microwave irradiation conditions was furnish regioselectively to the 6-hydroxyquinoline. The target compound was obtained in 77% yield via efficient domino reaction with a "one pot eleven steps".

Full text of DOI:10.1016/j.catcom.2013.07.029

Toward the synthesis of 6-hydroxyquinoline starting from glycerol via
improved microwave-assisted modified Skraup reaction
Hanen Saggadi, Denis Luart, Nicolas Thiebault, Isabelle Polaert, Lionel
Estel, Christophe Len
PII:
DOI:
Reference:
S1566-7367(13)00283-5
doi: 10.1016/j.catcom.2013.07.029
CATCOM 3589
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
10 April 2013
30 May 2013
10 July 2013
Please cite this article as: Hanen Saggadi, Denis Luart, Nicolas Thiebault, Isabelle Po-
laert, Lionel Estel, Christophe Len, Toward the synthesis of 6-hydroxyquinoline starting
from glycerol via improved microwave-assisted modified Skraup reaction, Catalysis Com-
munications (2013), doi: 10.1016/j.catcom.2013.07.029
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ACCEPTED MANUSCRIPT
Toward the synthesis of 6-hydroxyquinoline starting from
glycerol via improved microwave-assisted modified Skraup
reaction
a,b
a
a
b
b
Hanen Saggadi , Denis Luart , Nicolas Thiebault , Isabelle Polaert , Lionel Estel ,
a,
Christophe Len *
a
Transformations Intégrées de la Matière Renouvelable - EA 4297 UTC/ESCOM, Université
de Technologie de Compiègne, Centre de Recherches de Royallieu, BP 20529, rue Personne
de Roberval, F-60205 Compiègne cedex, France
b
Laboratoire de Sécurité des Procédés Chimiques – EA 4704 INSA Rouen, Avenue de
l’Université, F-76801 Saint-Etienne-du-Rouvray cedex, France
Corresponding author. Tel.: +33 3 4424 8828; fax: +33 3 4497 1591.
E-mail address: christophe.len@utc.fr .

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Abstract
Efficient modified Skraup reaction and Bamberger rearrangment in neat water was developed
using nitrobenzene and inexpensive, abundant and environmentally-friendly glycerol under
microwave irradiation conditions to furnish regioselectively the 6-hydroxyquinoline. The
target compound was obtained in 77% yield via efficient domino reaction with an “one pot
eleven steps”.
Keywords
glycerol – Skraup – Bamberger – aqueous catalysis – 6-hydroxyquinoline – microwaves –
domino reaction
Highlights
Efficient modified Skraup reaction and Bamberger rearrangement
Modified Skraup reaction without As O5
2
Synthesis of 6-hydroxyquinoline under microwave irradiation conditions
Synthesis of 6-hydroxyquinoline via a domino reaction

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1
. Introduction
Quinoline derivatives represent an important class of heterocycles. The quinoline ring system
occurs in various natural products, especially in alkaloids such as quinine for the treatment of
malaria [1] and thereafter in many synthetic pharmaceutical agents such as chloroquine and
mefloquine. In addition, the quinoline skeleton is often used for the design of many ligands
[
2] and functional material [3]. Among the quinoline derivatives, 6-hydroxyquinoline (5) is a
starting heterocycle for pharmaceutical research and electronic material [4].
The structural core of quinoline has generally been synthesized by various conventional
reactions such as Skraup reaction [5], Doebner-Miller reaction [6], Friedlander reaction [7],
Pfitzinger reaction [8], Conrad-Limpach reaction [9], Combes reaction [10]. The major
advantages of the Skraup reaction are its simple experimental protocol and the use of glycerol
(1) as the main byproduct of the biodiesel industry. Indeed, starting from glycerol (1), aniline
analogues, strong acid and various oxidants, the corresponding quinoline derivative is
obtained in medium yield. However, several drawbacks are observed such as harsch reaction
conditions, requiring high temperature (>200°C) and highly acidic conditions resulting in
lower yields of products due to the tedious isolation from complex reaction mixtures. It is also
noted that, using the Skraup reaction, only the benzene ring of the quinoline may be
substituted. Accordingly, the substitution at the 5-, 6-, 7- and 8- positions depends on the
choice of the substituted aniline used as starting material.
Due to recent efforts in developing green chemistry and sustainable development for
academic and industrial research, chemists have recently established catalytic reactions based
on renewable resources, atom economy, less hazardous chemical syntheses, safer solvents,
auxiliaries and alternative technologies such as microwave irradiations. The chemical industry
demands short reaction time, high selectivity and these objectives can be obtained via
microwave irradiation as a practical alternative to conventional heating. In this respect, the
microwave-assisted Skraup reaction was developed for the synthesis of quinoline analogues
using 2,6-diaminotoluene, glycerol, arsenic(V) oxide and sulfuric acid at 132°C for 33
minutes. The target heterocycle was prepared in 32% yield [11].
Using the Skraup methodology, the 6-hydroxyquinoline (5) was obtained starting from the 4-
hydroxyaniline (6) in presence of glycerol (1) in acidic media [12]. H SO 50%, 4-
2
4
hydroxyaniline (6), glycerol (1) and iodine were mixed at 150°C under 1.5 bar for 8 hours and
furnished the heterocycle 5 in 82% yield. It was notable that the most classical protocol for
the synthesis of 6-hydroxyquinoline (5) did not build the quinoline core but started from 6-
substituted quinoline having either a chlorine atom [13], a methoxy group [14] or a benzyl

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group [15]. In 2010, Cho et coll. described the synthesis of various quinoline analogues by
reduction of the nitroarene followed by propanol group transfer from tris(3-hydroxypropyl)-
amine and cyclization under heterogeneous Pd-C catalysis [16]. For example, the 6-
hydroxyquinoline (5) was obtained in 66% yield starting from 4-nitrophenol (7). In order to
provide a protocol for the synthesis of 6-hydroxyquinoline (5) according to the principles of
green chemistry and sustainable development, modified Skraup reaction was examined and
toxic reagents such as As O were removed.
2
5
2
.1 General
All reactants were obtained from Acros Organics and were used as received without further
purification. Solvents were purchased from Carlo Erba. Chromatography was performed on a
neutral silica gel.
Microwave experiments were conducted in a commercial microwave reactor especially
designed for synthetic chemistry. Monowave300 (Anton Paar, Austria) is a mono-mode cavity
with a microwave power delivery system ranging from 0 to 850 W. The temperatures of the
reactions were mainly monitored via contactless infrared pyrometer, which was calibrated in
control experiments with a fibre-optic contact thermometer. Reaction time described
-1
corresponds to 40 minutes (a heating ramp of 7°C.min for 30 minutes then 220°C for 10
minutes). Sealed vessels and magnetic stir bar inside the vessel were used. Temperature and
power profiles were monitored in both cases through the software provided by the
manufacturer.
2
.2. Characterization
NMR spectra of products were recorded on a Bruker instrument operating at 400.13 MHz for
proton and 100.62 MHz for carbon. The qualitative and quantitative analysis of the reactants
and products was performed by liquid chromatography. Products were identified by a
comparison with authentic samples.
2
.3. Typical procedure for the modified Skraup reaction
A 30 mL sealed vessel was charged with nitrobenzene (3, 10 mmol), glycerol (1, 40 mmol,
.0 eq), H SO (30 mmol, 3 eq) in water (7.4 mL). The mixture was irradiated with a power
4
2
4
-1
high enough to reach the predicted temperature with a heating ramp of 7°C.min , then 220°C
for 10 minutes. After cooling at room temperature, pH was adjusted at 8-9 by addition of

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NaOH and the reaction mixture was extracted with ethyl acetate (3 x 20 mL). The combined
organic layers were dried over MgSO , filtered and evaporated under reduced pressure. The
4
crude residue was purified by column chromatography (cyclohexane/EtAc, 1:1, v/v) on silica
gel yielding the 6-hydroxyquinoline (5, 1.12 g, 77%).
3
. Results and discussion
In the first set of experiments, the most toxic and poisonous reagents like arsenic oxide used
in the Skraup reaction were removed and water was added as green solvent. In this regards,
the reaction of glycerol (1) (4 equiv) with aniline (2) (0.5 equiv) and nitrobenzene (3) (0.5
equiv) in presence of sulfuric acid (3 equiv) was carried out as a model reaction in sole water
at 220°C under microwave irradiations (Scheme 1). The mixture was irradiated with a power
-1
high enough to reach the predicted temperature with a heating ramp of 7°C.min , then 220°C
for 10 minutes. In the present work, this microwave irradiation protocol was always used. In
our hands, a mixture of two quinolines was obtained, the parent quinoline (4) in 42% yield
and traces of 6-hydroquinoline (5) (Scheme 1). The presence of traces of 6-hydroxyquinoline
(5) is interesting in two titles. In a first part, 4-hydroxyaniline (6), usually used as starting
product for the preparation of heterocycle 5 [12], was not added to the reaction. In the second
part, in the classical Skraup reaction, nitrobenzene (3) was used as oxidant and did not allow
the synthesis of 6-hydroxyquinoline (5).
H SO
4
H O
2
OH
2
NH2
NO2
HO
OH
+
+
+
MW
N
N
OH
1
2
3
4
5
Scheme 1. Synthesis of quinoline and 6-hydroxyquinoline.
As a first conclusion, the substitution of the benzene ring at the 6- position by a hydroxyl
group was linked either to the presence of nitrobenzene and/or the experimental conditions.
The Skraup reaction was tested without aniline (2). In our hands, the reaction of glycerol (1)
(4 equiv) with nitrobenzene (3) (1 equiv) in presence of sulfuric acid (3 equiv) furnished
regioselectively the 6-hydroxyquinoline (5) in 60% without traces of quinoline (4) (Table 1,
entry 1). Lowering the temperature from 220°C to 150°C decreased the yield of the target 6-
hydroxyquinoline (5) (Table 1). Less than 200°C, the formation of acrolein from glycerol (1)

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was not efficient and did not permit the formation of the target heterocycle 5 in good yield.
Considering the yield obtained at 220°C, this temperature was chosen.
Table 1
Variation of temperature for the modified Skraup reaction starting from glycerol (1) and
a
nitrobenzene (3) in water under microwave irradiations.
H SO
H O
2
OH
2
4
NO2
HO
OH
+
MW
N
OH
1
3
5
Temp.
°C)
Yield
Entry
(
(%)
60
57
30
17
3
1
2
3
4
5
6
220
210
200
190
175
150
1
a
Reaction conditions: 1 (40 mmol), 3 (10 mmol), H SO (30 mmol), water (3.70 mL), 40 min
2
4
-1
under microwave activation (heating ramp = 7°C.min then predicted temperature for 10
min).
In view of these preliminary results, the use of nitrobenzene (3) as the sole source of aromatic
ring assumed that (i) the nitro group was reduced in our experimental conditions; (ii) the
hydrogen atom in para position of the arene 3 was substituted by an hydroxyl group.
In search of a more efficient catalyst, the next step consisted of examining different acids such
as FeCl , H SO /FeCl , FeCl /AcOH, Fe (SO ) , H SO /Fe (SO ) and by varying their
3
2
4
3
3
2
4 3
2
4
2
4 3
concentration (from 1.0 equiv to 5 equiv) using the experimental conditions described above
Table 1, entry 1). Even though all the acid or mixture of acids promoted the formation of 6-
hydroxyquinoline (5), none of these acids was as good as H SO (3 equiv).
(
2
4

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Starting from the nitrobenzene (3), the formation of 6-hydroxyquinoline (5) may be due to the
presence of water as solvent as mentioned above. The concentration of the starting materials:
glycerol (1) and nitroarene 3 in water has been modulated to investigate the best ratio (Table
2
). The presence of added water was not required to obtain the 6-hydroxyquinoline (5) due to
the continuous formation of water by double dehydratation of glycerol (1) to acrolein (Table
2
6
2
, entry 1). In this case, the yield of heterocycle 5 was low (25%). However, the yields of the
-hydroxyquinoline (5) were significantly improved when water was added as solvent (Table
, entries 2-20). In our hands, the higher yield was obtained by mixing glycerol (1) (4 equiv)
with nitrobenzene (3) (1 equiv) in presence of sulfuric acid (3 equiv) in water (7.5 mL, 41.7
equiv).

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Table 2
Variation of the concentration of the starting materials 1 and 3 in water for the modified
a
Skraup reaction under microwave irradiations.
H SO
H O
2
OH
2
4
NO2
HO
OH
+
220°C
N
OH
MW
1
3
5
a
H O
H O
(equiv)
Yield
(%)
2
2
Entry
(
mL)

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1
2
3
3
4
5
6
7
8
9
0
0
25
15
16
20
30
33
38
42
45
53
57
60
62
65
68
68
71
75
75
77
77
0.25
0.50
0.75
1.00
1.25
1.50
1.75
2.00
2.50
3.00
3.50
4.00
4.50
5.0
1.4
2.8
4.2
5.6
6.9
8.3
9.7
11.1
13.9
16.7
19.4
22.2
25.0
27.8
30.5
33.3
36.1
38.9
41.7
44.4
1
0
1
2
3
4
5
6
7
8
9
0
1
1
1
1
1
1
1
1
1
2
5.5
6.0
6.5
7.0
7.5
8.0
a
Reaction conditions: 1 (40 mmol), 3 (10 mmol), H SO (30 mmol), water (0-8.0 mL), 40 min
2
4
-1
under microwave activation (heating ramp = 7°C.min then predicted temperature for 10
min).
In order to reduce the quantity of reagents, the concentration of glycerol was decreased (Table
3
). In our hands, the modified Skraup reaction using glycerol (1) (3 equiv) with nitrobenzene

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(3) (1 equiv) in presence of sulfuric acid (3 equiv) in water (0-5.5 mL) furnished moderate
yield. The optimal one was 41% yield using 4.5 mL (25 equiv) of water. It seems clear that
the limiting step of the modified Skraup reaction is the formation of acrolein and the presence
of a large amount of glycerol is required (4 equiv vs 3 equiv).
Table 3
Variation of the concentration of the starting materials 1 and 3 in water for the modified
a
Skraup reaction under microwave irradiations.
H SO
H O
2
OH
2
4
NO2
HO
OH
+
220°C
N
OH
MW
1
3
5
a
H O
H O
(equiv)
Yield
(%)
2
2
Entry
(
mL)
1
2
3
4
5
6
7
8
9
0
0
10
25
29
32
34
34
38
40
41
40
41
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
5.6
8.3
11.1
13.9
16.7
19.4
22.2
25.0
27.8
30.5
1
1
0
1
a
Reaction conditions: 1 (30 mmol), 3 (10 mmol), H SO (30 mmol), water (0-5.5 mL), 40 min
2
4
-1
under microwave activation (heating ramp = 7°C.min then predicted temperature for 10
min).

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The same experiment was applied under conventional heating for 24 hours yielding only
traces of compound 5 (<3% yield). In our hands, only the MW irradiation permitted to furnish
the target compound in significant yield.
Using the optimized method (Table 2, entry 19), 4-nitrophenol (7) and 4-hydroxyaniline (6) as
aromatic sources were tested. Starting from 4-nitrophenol (7), the 6-hydroxyquinoline (5) was
obtained in 55% yield while from 4-hydroxyaniline (6) the target heterocycle 5 was obtained
in 27% yield (Table 4). In our case, the use of nitrobenzene (3) as starting material provided
the 6-hydroxyquinoline (5) with the best performance (77% yield).
Table 4
Variation of the nitroarenes for the modified Skraup reaction in water under microwave
a
irradiations.
OH
H SO
OH
2
4
H O
2
HO
OH
+
220°C
N
OH
R
MW
1
6-7
5
a
Yield
Entry Nitroarenes
R
(%)
1
2
6
7
NH2
NO2
27
55
a
Reaction conditions: 1 (30 mmol), 6-7 (10 mmol), H SO (30 mmol), water (0-7.36 mL), 40
2
4
-1
min under microwave activation (heating ramp = 7°C.min then predicted temperature for 10
min).
One plausible mechanism for the modified Skraup reaction was envisaged and might involve
the formation N-hydroxylaniline (8). It was notable that this one permitted to afford
industrially the 4-hydroxyaniline (6) via the Bamberger reaction. In our conditions, the
reduction of the nitrobenzene (3) in the presence of glycerol (1) furnished the N-
hydroxylaniline (8). After O-protonated of compound 8, elimination of a molecule of water
afforded the nitrenium ion 9. Intermediate 9 may then react with a molecule of water to

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furnish the 4-hydroxyaniline (6) (Scheme 2, step 1). The formation of acrolein from glycerol
(1) by double dehydratation in acidic conditions is a known mechanism (Scheme 2, step 2).
The regioselective 1,4-addition of 4-hydroxyaniline (6) to acrolein afforded the corresponding
aldehyde 10. After protonation of aldehyde 10, the dehydrative ring closure obtained in two
steps by intramolecular addition and dehydratation was followed by oxidation of the aromatic
ring conducted to the final heterocycle 5 (Scheme 1, step 3). The proposed mechanism
permitted to explain the synthesis of 6-hydroquinoline (5) via modified Skraup reaction in an
“one pot eleven steps” is a typical domino reaction. It was noteworthy that an increase of
water led to an increase in the 6-hydroxyquinoline (5) yield (Tables 2 and 3). It seemed
reasonable that this effect was due to the hydroxylation step from compound 9 to the 4-
hydroxyaniline (6).
OH
+
dehydratation
OH
OH
reduction
NO2
OH
OH
O
1
3
STEP 2
STEP 1
NH
OH
OH
8
dehydratation
protonation
O
NH
O
OH
+
+
H
+
H
NH
dehydratation
NH2
H +
H O
2
STEP 3
6
1
,4-addition
NH
+
hydroxylation
O
OH
9
HO
HO
N
H
N
H
10
protonation
dehydratation
then
H
H
+
O
O
H
intramolecular
addition
HO
HO
HO
oxydation
N
H
N
H
N
+
5
Scheme 2. Plausible mechanism for the synthesis of 6-hydroxyquinoline.

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4
. Conclusion
In summary, the classical Skraup reaction was modified to obtain the 6-hydroxyquinoline in
7% yield starting from nitrobenzene as sole source of aromatic compound. From the view
7
point of green chemistry, the toxic reagents like arsenic(V) oxide was removed, water was
used as green solvent and alternative microwave irradiations were developed. Our
optimization furnished one efficient domino reaction with an “one pot eleven steps” using
only glycerol, nitrobenzene, sulphuric acid and water via modified Skraup reaction and
Bamberger rearrangement. This process permitted: (i) the reduction of nitrobenzene to 4-
hydroxyaniline via the successive formation of N-hydroxylaniline and aromatic nucleophilic
substitution by elimination – addition; (ii) the double dehydratation of glycerol to acrolein;
(iii) the addition of 4-hydroxyaniline to acrolein. To the best of our knowledge, this is the first
time that the 6-hydroxyquinoline has been obtained under such green conditions.
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Graphical abstract