Solvent-free synthesis of polyhydroquinoline and 1,8-dioxodecahydroacridine derivatives through the Hantzsch reaction catalyzed by a natural organic acid: A green method

Article abstract of DOI:10.1080/00397911.2017.1316406

Solvent-free and high yielding one-pot synthesis of 1,8-dioxodecahydroacridine and polyhydroquinoline derivatives have been described through Hantzsch condensation of various aldehydes, ammonium acetate with cyclic 1,3-dicarbonyl compounds and ethyl aceto

Full text of DOI:10.1080/00397911.2017.1316406

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Solvent-free Synthesis of Polyhydroquinoline and
1,8-dioxodecahydroacridine Derivatives via the
Hantzsch Reaction Catalyzed by a natural organic
acid: A green method
Imène Sehout, Raouf Boulcina, Boudjemaa Boumoud, Taous Boumoud &
Abdelmadjid Debache
To cite this article: Imène Sehout, Raouf Boulcina, Boudjemaa Boumoud, Taous Boumoud
& Abdelmadjid Debache (2017): Solvent-free Synthesis of Polyhydroquinoline and 1,8-
dioxodecahydroacridine Derivatives via the Hantzsch Reaction Catalyzed by a natural organic acid:
A green method, Synthetic Communications, DOI: 10.1080/00397911.2017.1316406
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1316406
View supplementary material
Accepted author version posted online: 12
Apr 2017.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20
Download by: [University of Pennsylvania]
Date: 12 April 2017, At: 11:11

Solvent-free Synthesis of Polyhydroquinoline and 1,8-dioxodecahydroacridine
Derivatives via the Hantzsch Reaction Catalyzed by a natural organic acid: a green
method
Imène Sehout1, Raouf Boulcina1, Boudjemaa Boumoud1, Taous Boumoud1, Abdelmadjid
Debache1
1Laboratoire de synthèse de molécules d’intérêts biologiques, Faculté des Sciences
Exactes, Université Frères Mentouri Constantine 1, Algérie
Corresponding author Abdelmadjid Debache, Email: a_debache@yahoo.fr
Abstract
Solvent-free and high yielding one-pot synthesis of 1,8-dioxodecahydroacridine
and polyhdroquinoline derivatives have been described via Hantzsch
condensation of various aldehydes, ammonium acetate with cyclic 1,3-dicarbonyl
compounds and ethyl acetoacetate in a very simple, efficient, and environmentally
benign method using ascorbic acid as a nontoxic organocatalyst.
Graphical Abstract:
KEYWORDS: Polyhydroquinoline, 1,8-dioxodecahydroacridine, solvent-free
conditions, ascorbic acid, Hantzsch reaction.
1

INTRODUCTION
The development of solvent-free organic synthetic methods has become an important
research area, aiming to make the syntheses simpler, to save energy and to prevent
hazardous solvent waste and toxicity in chemical processes.[1] Overwise, to avoid
contamination of products with metals, especially in pharmacology, the use of metal-free
catalysts is more appropriate because of their less hazardous properties and nontoxicity.
Undoubtedly, the most suitable and convenient synthetic strategies of diverse and
complex compounds, as well as small and drug-like heterocycles, are those involving
multicomponent reactions which have manifested themselves as a powerful tool for the
rapid introduction and expansion of molecular diversity.[2-3] Thus, it goes without saying
that the use of atom-economical multicomponent reactions (MCRs), together with the
employment of solvent-free conditions in the presence of a metal free catalyst must be
considered to be a facile and effective synthetic strategy of heterocyclic compounds with
important bioactivities as well as an ecological point of view.
It has been reported that a considerable number of 1,4-dihydropyridine derivatives
bear wide range of biological activities.[4] Among these compounds, polyhydroacridine-
1,8-diones are poly functionalized derivatives of DHPs containing an acridine moiety,
have a wide range of pharmacological properties such as anticancer[5], fungical[6],
calcium -blockers[7], antitumor,[8] antileukimic.[9] On the other hand,
polyhydroquinoline derivatives, having a 1,4-dihydropyridine moiety, possess also some
interesting biological properties and are used as antimalarial, antibacterial , anti-
2

asmathic, antiinflammatory and they have also exhibited excellent results in
chemotherapy of cancer.[10]
In view of the importance of polyhydroquinoline and 1,8-dioxodecahydroacridine
derivatives, chemists have developed several
methods for their synthesis which
involves a three-component reaction between an aromatic aldehyde, dimedone (or 1,3-
cyclohexanedione) and ammonium acetate for 1,8-dioxodecahydroacridines or a four-
component reaction, adding ethyl acetoacetate, for polyhydroquinolines in the presence
of a variety of catalysts such as 1,3-di (bromo or chloro)-5,5-dimethylhydantoin,[11]
CH3SO3H,[12] tetrabutylammonium hexatungstate,[13] Indion-860,[14] silica boron-sulfuric
acid,[15] nano titan dioxyde,[16] SiO2/ZnCl2,[17] ionic liquid with multi-SO3H groups,[18]
protic pyridinium ionic liquid,[19] Caesium carbonate,[10] Ceric ammonium nitrate,[20] L-
Proline,[21] organocatalysts,[22] Nickel nanoparticules,[23] Sulphaminic acid,[24] Magnesium
oxide,[25] Thiamine hydrochloride,[26] Tin oxide,[27] La2/TFE,[28] Cd(NO3)2.4H2O,[29]
Carbon-based solid acid.[30]
However, most of the reported methodologies still have certain limitations in terms
of toxicity of solvents and catalysts, anhydrous organic solvents, restrictions for
large scale applications, excessive amounts of catalysts and generation of large
amounts of toxic wastes in scaling up for industrial, in some cases, catalysts are
expensive and harmful to human being and environment. Thus, the development of a
simple, safe and efficient method for the synthesis of such compounds is necessary.
3

As a part of our interest in the development of highly expedient methodologies for the
synthesis of heterocyclic compounds of biological importance[31-33] and with an
objective to nurture a green approach and to refrain from the use of metal containing
catalysts, we report herein, the catalytic role of ascorbic acid in the synthesis of
1,8-dioxodecahydroacridine and polyhydroquinoline derivatives via multi-component
condensation of aldehydes, ammonium acetate with cyclic 1,3-diketone
compounds (dimedone or 1,3-cyclohexanedione) or with cyclic 1,3-diketone
compounds (dimedone or 1,3-cyclohexanedione) and ethyl acetoacetate respectively,
in the presence of catalytic amounts of ascorbic acid under solvent-free
conditions (Scheme 1).
RESULTS AND DISCUSSION
To optimize the reaction conditions, the reaction of benzaldehyde (1 mmol),
dimedone (2 mmol), and ammonium acetate (1 mmol) in the presence of
ascorbic acid (10 mol%) was selected as a model (Scheme 1). The reaction was carried
out in various solvents and under solvent-free conditions. As shown in Table 1 (entries
1-5), in comparison to conventional methods, the yields of the reaction under solvent-
free conditions are greater. Encouraged by this result, we carried out the model
reaction under the previously mentioned conditions using different quantities of
catalyst at different temperatures. The results are summarized in Table 1.
After systematic screening, we observed that with an amount more than 5 mol% of the
catalyst (Table 1, entries 6-8) the reaction either did not complete or the starting
4

material or the product may have been destroyed during the reaction when
excess amount of ascorbic acid was used in the exothermic reaction and that 5
mol% ascorbic acid was sufficient to catalyse the reaction effectively (Table 1,
entry 9). When we carried out the reaction at room temperature, the reaction
proceeded very slowly to give very poor yields (Table 1, entry 11).
Having established the optimized reaction conditions, and to evaluate the efficacy and
applicability of our protocol, we have carried out the multicomponent condensation using
a variety of structurally distinct aldehydes and β-diketone. The results are depicted in
Tables 2 and 3.
As shown in this Table, both electron rich and electron deficient aromatic aldehydes as
well as heterocyclic ones such 2-thiophenecarboxaldehyde afforded the desired 1,8-
dioxodecahydroacridine in good to excellent yields (Table 2, entries 1−10), however, the
reaction with aliphatic aldehyde, the time was prolonged and the yield of the product was
very low (Table 2, entry 11).
After successfully synthesizing a series of 1,8-dioxodecahydroacridine derivatives, we
turned our attention towards the four component reaction of cyclic 1,3-diketone,
aldehyde, ethyl acetoacetate, and ammonium acetate to prepare the polyhydroquinoline
derivatives under similar reaction conditions (Scheme 1).
5

In this regard aromatic aldehydes reacted smoothly under similar conditions to give the
corresponding polyhydroquinolines in high yields as summarized in Table 3.
Scheme 2 shows a tentatively proposed mechanism for the synthesis of 1,8-
dioxodecahydroacridine and polyhydroquinoline derivatives. Ascorbic acid facilites the
enolization of a molecule of the 1,3-diketone and changes the aldehyde into convenient
electrophile by protonation and intermediates 1 and 2 are respectively obtained and react
together to give the intermediate 3 by a Knoevenagel-type reaction. Furthermore a second
1,3-diketone molecule or an ethyl acetoacetate molecule undergoes enolization under
influence of ascorbic acid to yield intermediate 4. Then a Michael-type reaction takes
place between 3 and 4. The resulting intermediate 5 reacts with ammonium acetate to
yield imine 6 which undergoes an intramolecular cyclisation and dehydratation to yield
the expected product 8.
CONCLUSION
In conclusion, we have developed a simple and efficient method for the synthesis of 1,4-
dihydropyridine derivatives via Hantzsch condensation using ascorbic acid as catalyst
under solvent-free conditions. The mildness of the conversion, the experimental
simplicity, the compatibility with various functional groups, the inexpensive reagents, the
metal-free catalyst and the easy workup procedure employed, make this procedure very
attractive to synthesize a variety of these derivatives.
6

EXPERIMENTAL DETAILS
General Procedure For The Synthesis Of 1,8-Dioxodecahydroacridine Derivatives
(6a-K)
A mixture of aldehyde (1 mmol), dimedone (2 mmol), ammonium acetate (1 mmol) and
ascorbic acid (5 mol %) was stirred at 80°C under solvent free conditions for the
appropriate time (Table 2). After complete conversion as indicated by TLC, the reaction
mixture was cooled to room temperature, poured onto ice-cold water (10 ml) and stirred
for about 10 minutes. The formed solid filtered off, washed with cold water and purified
by simple crystalization in ethanol.
Spectral Data For Selected Products
3,3,6,6-Tetramethyl-9-Phenyl-3,4,6,7-Tetrahydroacridine-1,8(2H,5H,9H,10H)-Dione
(6a)
M.p.: 192-194 °C ; lit.[30] 192-196 °C; IR (KBr, cm-1) ν : 3278.8, 2954.7, 1631.7, 1365.5;
1H NMR (250 MHz, DMSO-d6) δ: 7.65 (s, 1H, NH), 7.35-7.05 (m, 5H), 5.08 (s, 1H,
C9H), 2.32-2.12 (m, 8H, 4CH2), 1.06 (s, 6H, 2CH3), 0.95 (s, 6H, 2CH3); 13C NMR 562.5
MHZ, DMSO-d6) δ: 195.8, 148.9, 146.6, 128.0, 127.9, 126.0, 113.3, 50.9, 40.8, 33.6,
32.6, 29.5, 27.1.
3,3,6,6-Tetramethyl-9-(Thiophen-2-Yl)-3,4,6,7-Tetrahydroacridine-
1,8(2H,5H,9H,10H)-Dione (6d)
M.p.: 236-238 °C; IR (KBr, cm-1) ν: 3274.9, 2958.6, 1593.1, 1477.4, 1373.2; 1H NMR
(250 MHz, DMSO-d6) δ: 12.31 (s, 1H, NH), 7.12-7.10 (m, 1H), 6.87 (dd, J = 5.5 Hz,
7

1H); 6.64-6.63 (m, 1H), 5.63 (s, 1H, C9H), 2.25-2.40 (m, 8H, 4CH2), 1.22 (s, 6H, 2CH3),
1.10 (s, 6H, 2CH3); 13C NMR (62.5 MHz, DMSO-d6) δ: 189.9, 143.7, 126.4, 124.6,
123.5, 116.0, 47.0, 46.3, 31.2, 30.4,29.9, 26.8; HRMS (MS-ESI+, M/Z): [M+H]+
calculated for (C21H26NO2S+): 356.16842, found: 356.1679.
General Procedure For The Synthesis Of Polyhydroquinoline Derivatives (7a-J)
A mixture of aldehyde (1 mmol), cyclic 1,3-diketone (1 mmol), ethyl acetoacetate (1
mmol), ammonium acetate (1 mmol) and ascorbic acid (5 % mol) was stirred at 80°C
under solvent free conditions for the appropriate time (Table 3). After complete
conversion as indicated by TLC, the reaction mixture was cooled to room temperature,
poured onto ice-cold water (10 ml) and stirred for about 10 minutes. The formed solid
was filtered off, washed with cold water and purified by simple crystallization in ethanol.
Spectral Data For Selected Products
Ethyl 2,7,7-Trimethyl-5-Oxo-4-Phenyl-1,4,5,6,7,8-Hexahydroquinoline-3-
Carboxylate (7a)
M.p.: 205-207 °C; lit.[27] 203-205 °C; IR (KBr,.2 cm-1) ν : 3286.5, 2962.5, 1697, 1612.4,
1
1485.1; H NMR (250 MHz, DMSO-d6) δ: 0.85 (s, 3H, CH3), 1.01 (s, 3H, CH3), 1.14(t,
J = 7.1, 3H, CH3), 2.06 (dd, J = 16.2, 1H, CH2), 2.13 (dd, J = 16.1, 1H, CH2), 2.28 (s, 2H,
CH2), 3.18 (s, 3H, CH3), 3.98 (q, J = 7.1, 2H, CH2), 4.91 (s, 1H, C4H), 6.90-7.22 (m,
5Harom); 13C NMR (62.5 MHz, DMSO-d6) δ: 194.5, 166.8, 149.1, 147.1, 144.2, 127.2,
127.0, 125.0, 110.2; 104.0, 58.7, 50.1, 35.7, 31.7, 28.9, 26.3, 18.0, 13.6.
8

Ethyl 2,7,7-Trimethyl-5-Oxo-4-(Quinolin-2-Yl)-1,4,5,6,7,8-Hexahydroquinoline-3-
Carboxylate (7f)
M.p.: 251-253 °C; IR (KBr, cm-1) ν: 3294.2, 2943.2, 1693.4, 1492.8; 1H NMR (250
MHz, DMSO-d6) δ: 0.93 (s, 3H, CH3), 1.03 (s, 3H, CH3), 1.16 (t, J = 6.9, 3H, CH3), 2.41
(s, 2H, CH2), 2.39 (s, 3H, CH3), 3.97-4.12 (m, 2H, CH2), 5.48 (s, 1H, C4H), 8.82 (s, 1H,
NH); 13C NMR (62.5 MHz, DMSO-d6) δ: 195.99, 167.68, 166.43, 150.30, 147.79,
145.55, 135.37, 129.01, 127.98, 127.64, 125.79, 124.58, 124.30, 110.76, 104.46, 59.92,
50.77, 41.04, 40.63, 33.17, 28.59, 28.3, 19.22, 14.38; HRMS (MS-ESI+, M/Z): [M+Na]+
calculated for (C24H26N2O3Na+) 413.18411, found: 413.1836.
ACKNOWLEDGEMENTS
We gratefully acknowledge the MESRS (Ministère de l’Enseignement Supérieur et de la
Recherche Scientifique, Algérie) for financial support.
SUPPORTING INFORMATION
Full experimental detail and 1H and 13C NMR spectra can be found via the
“Supplementary Content” section of the article’s Web page.
REFERENCES
[1] Tanaka, K. Solvent-free organic synthesis, Wiley, 2009.
[2] Orru, R. V. A.; Ruijter, E. Topics in Heterocyclic Chemistry, Vol. 23 and 25, 2010.
[3] Zhu, J.; Bienaymé, H. Multicomponent reactions. Wiley, 2005.
[4] Khedkar, S. A.; Auti, P. B. Med. Chem. 2014, 14, 282-290.
9

Sepehri, S. ; Sanchez, H. P. ; Fassihi, A. J. Pharm. Pharm. Sci. 2015, 18, 1-52.
[5] Wainwright, M. J. J. Antimicrob. Chemother. 2001, 47,1-13.
[6] Berkan, O.; Sarac, B.; Simsek, R.; Yildirim, S.; Sariogli, Y.; Safak, C. Eur. J. Med.
2002, 37, 519-523.
[7] Mikata, Y. ; Yokoyama, M. ; Mogami, K. ; Kato, M. ; Okura, I. ; Chikira, M. ; Yano,
S. Inorg. Chem. Acta 1998, 279, 51-57
[8] Cholody, W. M.; Horowska, B.; Paradziej-Lukowicz, J.; Martelli, S.; Konopa, J. J.
Med Chem. 1996, 39(5), 1028-1032.
[9] Lacasagne, A.; Buu-Ho, N. P. ; Daudel, R.; Zajdela, F. Adv. Cancer. Res. 1956, 4,
315-369.
[10] Samer, B. S.; Kamble, V. T. J. Chem. Pharm. Res. 2015, 7, 356-361. And references
therein.
[11] Maleki, B.; Tayebee, R.; Kermanian, M.; Ashrafi, S. S. J. Mex. Chem. Soc. 2013, 57,
290-297.
[12] Shen, Y-B.; Wang, G-W. Arkivoc 2008, xvi, 1-8.
[13] Davoodnia, A.; Khashi, M.; Tavakoli-Hoseini, N. Chin. J. Catal. 2013, 34, 1173-
1178.
[14] Goud, V. S.; Boruah, M. Der Pharm. Chem. 2015, 7, 316-322.
[15] Khalafi-Nezhad, A.; Panahi, F.; Mohammadi, S.; Foroughi, H. O. J. Iran Chem. Soc.
2013, 10 , 109-200.
[16] Rahmani, S.; Amoozadeh, A. J. Nanostruct. 2014, 4, 91-98.
[17] Soliman, H. A.; Mubarak, A. Y.; El-Merakabi, A.; Elmorsy, S. A. “SiO2/ZnCl2-
catalyzed heterocyclic Chem. Sci. Trans. 2014, 3, 819-825.
10

[18] Vahdat, S. M.; Akbari, M. Orient. J. Chem. 2011, 27, 1573-1580.
[19] Tajbakhsh, M.; Alinezhad, H.; Norouzi, M.; Baghery, S.; Akbari, M. J. Mol. Liq.
2013, 177, 44-48.
[20] Ko, S.; Yao, C-F. Tetrhedron 2006, 62, 7293-7299.
[21] Karade, N. N.; Budhewar, V. H.; Shinde, S. V.; Jadhav, W. N. Lett. Org. Chem.
2007, 4, 16-19.
[22] Kumar, A.; Maurya, R. M. Tetrahedron 2007, 63, 1946-1952.
[23] Sapkal, S. B.; Shelke, K. F.; Shingate, B. B.; Shingare, M. S. Tetrahedron Lett.
2009, 50, 1754-1756.
[24] Lambat, T.; Deo, S.; Dehmukh, T. J. Chem. Pharm. Res. 2014, 6, 888-892.
[25] Mierzace, H.; Isadyar, A.; Davoodnia, A.; Eshghi, H. “One-pot synthesis of J. Appl.
Chem.res. 2014, 8, 57-63.
[26] Gholap, S.; Gunjal, N. Iran. J. Catal. 2016, 6, 147-152.
[27] Vahdat, M. S.; Chekin, F. ; Hatami, M. ; Khavarpour, M. ; Baghery, S.; Roshan-
Kouhi, Z. Chin. J. Catal. 2013, 34, 758-763.
[28] Tekale, S. U.; Pagore, V. P. ; Kauthale, S. S.; Pawar, R. P. Chin. Chem. Lett. 2014,
25, 1149-1152.
[29] Tafer, R.; Boulcina, R.; Carboni, B.; Debache, A. J. Chin. Chem. Soc. 2012, 59,
1555-1560.
[30] Davoodnia, A.; Khojastehnezhad, A.; Tavakoli-Hoseini, N. Bull. Korean Chem. Soc.
2011, 32, 2243-2248.
[31] Amine Khodja, I.; Ghalem, W.; Dehimat, Z.; Boulcina, R.; Carboni, B.; Debache, A.
Synth. Commun., 2014, 44, 959-967.
11

[32] Ghalem, W.; Sedrati, R. H.; Benloucif, N.; Berrée, F.; Boumoud, B.; Debache, A.
Lett. Org. Chem. 2013, 10, 150-154.
[33] Amine Khodja, I.; Fisli, A.; Lebhour, O.; Boulcina, R.; Bomoud B.; and Debache, A.
Lett. Org. Chem. 2016, 13, 85-91.
12

Table 1. Optimisation of the reaction conditions for multicomponent synthesis of 1,8-
dioxodecahydroacridine (6a).
Entry Solvent
Catalyst
Temperature Time (h) Yield (%)a
(°C)
(mol %)
1
Acetonitrile
10
10
10
10
10
50
20
10
5
reflux
reflux
reflux
reflux
80
7
75
71
64
93
96
67
68
68
92
84
35
2
THF
7
3
Toluene
7
4
EtOH
7
5
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
7
6
80
4.5
4.5
4.5
4.5
4.5
4.5
7
80
8
80
9
80
10
11
5
60
5
rt
aIsolated yield.
13

Table 2. Ascorbic acid-catalyzed Hantzsch preparation of 1,8-dioxodecahydroacridine
derivatives (6a-k).
Entry Ar
R
Time (h)
Producta
6a
Yieldb
92
1
2
C6H5-
Me
Me
4.5
3
2-MeC6H4-
66
6b
3
4-MeC6H4-
2-thienyl
Me
Me
2.5
80
6c
4
5
4
4
83
91
6d
6e
4-NMe2C6H4- Me
6
7
8
9
4-ClC6H4-
4-BrC6H4-
4-MeOC6H4-
4-ClC6H4-
Me
Me
Me
H
3
89
88
95
85
6f
2.5
3.5
5.5
6g
6h
6i
10
11
4-NMe2C6H4-
Me2CH-
H
3.5
6
47
35
6j
Me
6k
aAll products were characterized from their spectroscopic (IR,1H NMR, and MS) data
and compared with authentic samples. bIsolated yields.
14

Table 3. Ascorbic acid-catalyzed Hantzsch preparation of polyhydroquinoline derivatives
(7a-j).
Entry Ar
C6H5-
R
Time (h)
Producta
7a
Yieldb
70
1
2
3
4
5
6
7
8
9
10
Me
Me
Me
H
4
4-HOC6H4-
4-MeOC6H4-
4-EtC6H4-
1.5
5
85
7b
99
7c
2
80
7d
3-ClC6H4-
H
3
81
7e
2-quinolyl-
4-Biphenyl-
3-MeOC6H4-
Me
Me
Me
4.5
5
96
7f
96
7g
2.5
2
85
7h
2-HO-3-MeO-C6H3- Me
2-HO-5-NO2C6H3- Me
88
7i
3
96
7j
aAll products were characterized from their spectroscopic (IR,1H NMR, and HRMS) data
and compared with authentic samples. bIsolated yields.
15

Scheme 1. One-pot synthesis of 1,8-dioxodecahydroacridine and polyhydroquinoline
derivatives
16

Scheme 2. Proposed reaction mechanism for formation of 1,8-dioxodecahydroacridine
and polyhydroquinoline derivatives
17