Combined thiourea dioxidewater: An effective reusable catalyst for the synthesis of polyhydroquinolines via hantzsch multicomponent coupling

Article abstract of DOI:10.1246/cl.2012.920

Thiourea dioxide in water was found to be an efficient and reusable organocatalytic system for the one-pot synthesis of polyhydroquinoline derivatives via the Hantzsch-type coupling of aldehyde, dimedone, acetoacetate, and ammonium acetate under mild reaction conditions. Operational simplicity, the use of an economically affordable catalyst, environmentally benign conditions, high product yields, and reusability of the catalyst system were the advantageous features of the developed method.

Full text of DOI:10.1246/cl.2012.920

doi:10.1246/cl.2012.920
920
Published on the web September 1, 2012
Combined Thiourea Dioxide-Water: An Effective Reusable Catalyst for the Synthesis
of Polyhydroquinolines via Hantzsch Multicomponent Coupling
Neeraj Kumar, Sanny Verma, and Suman L. Jain*
Chemical Sciences Division, CSIR-Indian Institute of Petroleum, Dehradun-248005, India
(Received May 16, 2012; CL-120420; E-mail: suman@iip.res.in)
Thiourea dioxide in water was found to be an efficient and
H2N
O
NH2
O
reusable organocatalytic system for the one-pot synthesis of
polyhydroquinoline derivatives via the Hantzsch-type coupling
of aldehyde, dimedone, acetoacetate, and ammonium acetate
under mild reaction conditions. Operational simplicity, the use
of an economically affordable catalyst, environmentally benign
conditions, high product yields, and reusability of the catalyst
system were the advantageous features of the developed method.
S
Thiourea dioxide (TUD)
R1
O
O
R2
O
CHO
O
O
O
TUD, H2O
R2
R
O
N
H
50 °C,
R
R1
R
O
NH4(OCOCH3)
R
4
1
2
3
Multicomponent coupling reactions (MCRs) have been
acknowledged as highly valuable synthetic tools for the
construction of complex molecular structures with minimum
reaction steps and simple workup procedures.1 Several advanced
techniques such as microwave reactions,2 sonication,3 organo-
catalysis,4 and combinatorial chemistry5 have been established
to accelerate these reactions. In the recent decades, increasing
environmental and economical considerations worldwide have
led to the search for enviroeconomic synthetic methods for
chemical reactions.6 In this regard, efforts are being made to
replace the expensive and hazardous metal-based catalysts with
organocatalysts, which are safe, less expensive, easily acces-
sible, harmless, and environmentally benign. In addition, the use
of water as the reaction medium is highly desired to make the
chemical reactions more environmentally as well as econom-
ically viable. During the course of our investigations, we have
established the use of thiourea dioxide,7 which can be easily
prepared by the oxidation of thiourea with hydrogen peroxide, as
an efficient organocatalyst for the synthesis of novel heterocyclic
compounds via multicomponent coupling reactions.8 As a
continuation of our work on multidisciplinary synthetic ap-
proaches, we now plan the synthesis of polyhydroquinolines
with various substituents. 4-Substituted 1,4-dihydropyridines
(1,4-DHPs), an important class of medicinal compounds,9
exhibit a number of therapeutic properties, i.e., they act as
Ca2+ channel blockers,10 vasodilators, and bronchodilators, and
as anti-atherosclerotic, antitumor, geroprotective, hepatoprotec-
tive, and antidiabetic agents.11,12 Conventionally, these com-
pounds are synthesized by the condensation of aldehyde with
ethyl acetoacetate and ammonia in acetic acid or alcohol.13,14
However, these methods suffer from several drawbacks such as
long reaction times, the need for toxic organic solvents, and low
yields. In recent years, several improved protocols, including
those involving the use of microwaves,15 organocatalysts,16-18
TMSCl-NaI,19 metal triflates,20 ionic liquids,21 ceric ammonium
nitrate,22 supported reagents, and polymers, have been devel-
oped. Again, the use of volatile solvents, high temperatures,23
expensive or hazardous catalysts that are harmful to the
environment, and long reaction times restricts the utility of
these efficient approaches. Consequently, there is scope for
further development of an efficient, environmentally benign, and
4k, R = CH3, R1 = H; R2 = CH3
4l, R = CH3, R1 = H; R2 = C2H5
4a, R = H, R1 = H; R2 = CH3
4b, R = H, R1 = H; R2 = C2H5
4c, R = H, R1 = 4-Cl; R2 = CH3
4d, R = H, R1 = 4-Cl; R2 = C2H5
4m, R = CH3, R1 = 4-Cl; R2 = CH3
4n, R = CH3, R1 = 4-Cl; R2 = C2H5
4o, R = CH3, R1 = 4-CH3; R2 = CH3
4p, R = CH3, R1 = 4-CH3; R2 = C2H5
4q, R = CH3, R1 = 4-OCH3; R2 = CH3
4r, R = CH3, R1 = 4-OCH3; R2 = C2H5
4s, R = CH3, R1 = 4-NO2; R2 = CH3
4t, R = CH3, R1 = 4-NO2; R2 = C2H5
4e, R = H, R1 = 4-CH3; R2 = CH3
4f, R = H, R1 = 4-CH3; R2 = C2H5
4g, R = H, R1 = 4-OCH3; R2 = CH3
4h, R = H, R1 = 4-OCH3; R2 = C2H5
4i, R = H, R1 = 4-NO2; R2 = CH3
4j, R = H, R1 = 4-NO2; R2 = C2H5
Scheme 1. TUD-catalyzed synthesis of polyhydroquinoline
derivatives.
cost-effective methodology for the synthesis of these valuable
compounds. Herein, we report a convenient, enviroeconomic,
and practical approach for the one-pot synthesis of polyhydro-
quinoline derivatives via the Hantzsch-type condensation of
aldehydes, dimedone, ethyl- or methyl acetoacetate, and am-
monium acetate in the presence of a catalytic amount of thiourea
dioxide in water under mild reaction conditions (Scheme 1). The
present methodology is particularly promising for the large-scale
preparation of polyhydroquinoline derivatives, where cost,
safety, and hazards are the prime factors of concern. The use
of thiourea dioxide (TUD) in water is advantageous as it allows
for recycling of the catalyst without any loss in activity.
At first, we carried out the reaction of benzaldehyde,
dimedone, ethyl acetoacetate, and ammonium acetate in the
presence of a catalytic amount of TUD (2 mol %) in water
(2 mL) at 50 °C to afford the corresponding polyhydroquinoline.
After the completion of the reaction, the product was isolated by
filtration. The aqueous layer containing TUD was washed with
diethyl ether to remove traces of the organic reactants. The
recovered aqueous solution of TUD was reused as such for the
subsequent reaction. The recyclability of the developed catalyst
was checked for seven runs (Table 1). The yield of the product
and reaction time were almost the same during these experi-
ments, indicating the efficient recycling of the aqueous solution
of TUD. In a controlled blank experiment, the reaction of
dimedone, benzaldehyde, and methyl acetoacetate in water did
not produce any product in the absence of TUD, even after a
Chem. Lett. 2012, 41, 920-922
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

921
Table 1. Results of recycling experiments24
Table 3. TUD-catalyzed synthesis of polyhydroquinolines in
large-scale reaction (gram-scale reaction)a
Run
1
2
3
4
5
6
7
93
Entry
R
R1
R2
Product
Yield/%b
Yield/%
94
94
92
93
93
92
1
2
3
4
5
H
H
H
H
H
H
H
4-Cl
4-Cl
4-CH3
CH3
C2H5
CH3
C2H5
CH3
4a
4b
4c
4d
4e
90
91
90
91
90
Table 2. TUD-catalyzed synthesis of polyhydroquinolinesa
Entry
R
R1
R2
Product
Yield/%b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
H
H
H
H
H
H
H
H
H
H
4-Cl
4-Cl
4-CH3
4-CH3
4-OCH3
4-OCH3
4-NO2
4-NO2
H
H
4-Cl
4-Cl
4-CH3
4-CH3
4-OCH3
4-OCH3
4-NO2
4-NO2
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
4a
4b
4c
4d
4e
4f
4g
4h
4i
92
94
91
91
92
92
91
91
89
89
92
94
94
93
91
91
90
90
85
85
aReaction conditions: aldehyde 2 (50 mmol), dimedone 1
(50 mmol), alkyl acetoacetate 3 (50 mmol), and ammonium
acetate (50 mmol), TUD (2 mol %, 1 mmol), H2O 100 mL as
b
solvent at 50 °C, reaction time 3 h. Isolated yields.
O
O
O
O
AcOH
+
+
H2O
S
C
+ NH4OAc
O
NH2
H2N
NH2
7
1
O
N
H
H
4j
4k
4l
O
O
S
O
O
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Ar
H
7
C
O
O
H2N
O
Michael
2
Addition
OEt
N
Ar
H
H
4m
4n
4o
4p
4q
4r
4s
4t
O
O
Ar
H
4
6
O
O
O
O
3
O
O
O
H
OH
O
S
C2H5
CH3
C2H5
CH3
Ar
NH
O
O
C
H2N
S
NH2
H2N
Scheme 2. Proposed mechanism for TUD-catalyzed poly-
hydroquinoline synthesis.
C2H5
aReaction conditions: aldehyde 2 (1 mmol), dimedone 1
(1 mmol), alkyl acetoacetate 3 (1 mmol), and ammonium
acetate (1 mmol), TUD (2 mol %), H2O 2 mL as solvent at
50 °C, reaction time 2 h.24 bIsolated yields.
is the ester enamine, which is produced by the condensation of 1
with ammonia (from ammonium acetate). Intermediates 6 and 7
react by the Michael addition to produce the final product 4. The
formation of Knoevenagel product 6 was confirmed by carrying
out the reaction of benzaldehyde and ethyl acetoacetate in the
presence of a catalytic amount of TUD in water.
prolonged reaction time (24 h). Next, we extended the reaction to
various aromatic, aliphatic, unsaturated, and heterocyclic alde-
hydes using the developed protocol. The results of these
experiments are presented in Table 2. All the substrates reacted
efficiently and afforded almost quantitative yields of the
corresponding polyhydroquinolines. The developed method is
very simple and convenient and can tolerate a variety of other
functional groups such as methoxy, nitro, hydroxy, and halides
under the given reaction conditions. Both electron-rich and
electron-deficient aldehydes reacted efficiently, leading to high
yields of the product. The use of just 2 mol % of TUD in water
was sufficient to push the reaction forward. Further increase in
the catalyst concentration (5 and 10 mol %) in water did not lead
to any significant improvement in the yield of the polyhydro-
quinolines. Further, we obtained the coupling products selec-
tively without any evidence for the formation of by-products.
We also attempted to use the developed protocol for the large-
scale synthesis of polyhydroquinolines; these results are summa-
rized in Table 3. As shown, the developed catalytic method was
found to be promising for the gram-scale synthesis of the desired
products.
In conclusion, we have described a very convenient,
environmentally benign, and practical approach for the prepa-
ration of polyhydroquinoline derivatives via the Hantzsch-type
condensation reaction by using an aqueous solution of thiourea
dioxide as a reusable catalyst. The important features of the
present method are as follows: the use of an inexpensive
catalyst, recyclability of the catalyst, easy experimental proce-
dures, easy workup, and high yields.
We gratefully acknowledge the kind permission of Director,
IIP, to publish these results. SV thanks CSIR for his fellowship.
Analytical division of the Institute is acknowledged for
assistance in the analysis (IR and NMR) of the products. DST,
New Delhi, is acknowledged for the research funding.
References and Notes
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Chem. Lett. 2012, 41, 920-922
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

922
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24 Experimental procedure for the synthesis of polyhydro-
quinoline derivatives 4: Into a stirred mixture of aromatic
aldehyde 2 (1 mmol), dimedone 1 (1 mmol), alkyl acetoace-
tate 3 (1 mmol), and ammonium acetate (2 mmol) was added
TUD (2 mol %). The reaction mixture was slowly heated to
50 °C and continued the reaction to the time as mentioned in
Table 2. Progress of reaction is monitored by TLC. After
completion of the reaction, the mixture was cooled to 10 °C.
The solid mixture so obtained was added in ethyl acetate to
recover the thiourea dioxide. The recovered catalyst was
isolated by filtration and reused for next experiments. The
filtrate was concentrated under reduced pressure and purified
by column chromatography. The crude product was finally
recrystallize from ethanol to afford the pure product. The
products were identified by comparing their physical and
spectral data with the reported compound.
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© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/