Solvent-free synthesis of dihydropyridines and acridinediones via a salicylic acid-catalyzed hantzsch multicomponent reaction

Article abstract of DOI:10.1080/00397911.2013.838791

A multicomponent Hantzsch synthesis of 1,4-dihydropyridines and acridinediones from commercially available aldehydes, ammonium acetate, and ethyl acetoacetate or dimedone, in the presence of salicylic acid as an efficient catalyst, in good yield and short reaction time is reported. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.838791

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Solvent-Free Synthesis of
Dihydropyridines and Acridinediones
via a Salicylic Acid–Catalyzed Hantzsch
Multicomponent Reaction
Imène Amine Khodja a , Wassima Ghalem a , Zineb Imene Dehimat a
Raouf Boulcina a , Bertrand Carboni b & Abdelmadjid Debache a
,
a Laboratoire de Synthèse des Molécules d'Intérêts Biologiques,
Click for updates
Département de Chimie , Faculté des Sciences Exactes, Université
de Constantine , Constantine , Algéria
b Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de
Rennes 1 , Campus de Beaulieu , Rennes , France
Accepted author version posted online: 08 Nov 2013.Published
online: 24 Feb 2014.
To cite this article: Imène Amine Khodja , Wassima Ghalem , Zineb Imene Dehimat , Raouf Boulcina ,
Bertrand Carboni & Abdelmadjid Debache (2014) Solvent-Free Synthesis of Dihydropyridines
and Acridinediones via a Salicylic Acid–Catalyzed Hantzsch Multicomponent Reaction, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
44:7, 959-967, DOI: 10.1080/00397911.2013.838791
To link to this article: http://dx.doi.org/10.1080/00397911.2013.838791
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Synthetic Communications1, 44: 959–967, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.838791
SOLVENT-FREE SYNTHESIS OF DIHYDROPYRIDINES
AND ACRIDINEDIONES VIA A SALICYLIC ACID–
CATALYZED HANTZSCH MULTICOMPONENT
REACTION
1
1
`
Imene Amine Khodja, Wassima Ghalem, Zineb Imene
Dehimat,1 Raouf Boulcina,1 Bertrand Carboni,2 and
Abdelmadjid Debache1
´
Laboratoire de Synthese des Molecules d’Interets Biologiques, Departement
de Chimie, Faculte des Sciences Exactes, Universite de Constantine,
1
`
´
´ ˆ
´
´
´
Constantine, Algeria
Sciences Chimiques de Rennes, UMR 6226 CNRS-Universite de Rennes 1,
2
´
Campus de Beaulieu, Rennes, France
GRAPHICAL ABSTRACT
Abstract A multicomponent Hantzsch synthesis of 1,4-dihydropyridines and acridinediones
from commercially available aldehydes, ammonium acetate, and ethyl acetoacetate or dime-
done, in the presence of salicylic acid as an efficient catalyst, in good yield and short reac-
tion time is reported.
[Supplementary materials are available for this article. Go to the publisher’s online edi-
tion of Synthetic Communications1 for the following free supplemental resource(s): Full
experimental and spectral details.]
Keywords Acridinediones; 1,4-dihydropyridines; Hantzsch; multicomponent; salicylic
acid
INTRODUCTION
Hantzsch 1,4-dihydropyridines (1,4-DHPs) constitute a class of compounds
with many derivatives, especially among natural products and bioactive agents.[1]
1,4-DHP derivatives have been found to be commercially useful molecules as
calcium channel blockers.[2–4] A number of these calcium antagonists have been
introduced as potential drugs for the treatment of congestive heart failure.[5,6]
Received July 12, 2013.
Address correspondence to Abdelmadjid Debache, Laboratoire de Synthese des Molecules
`
d’Interets Biologiques, Departement de Chimie, Faculte des Sciences Exactes, Universite de
´
´ ˆ
Constantine 1, 25000 Constantine, Algeria. E-mail: a_debache@yahoo.fr
´
´
´
´
959

960
I. A. KHODJA ET AL.
Cerebrocrast, a dihydropyridine derivative, has been introduced as a neuroprotective
agent.[7] Together with calcium channel blocker and neuroprotective activity, a
number of dihydropyridine derivatives have been found to be vasodilatory, antihy-
pertensive, bronchodilatory, antiatherosclerotic, hepatoprotective, antitumor, anti-
mutagenic, geroprotective, antidiabetic, and antiplatelet aggregation agents.[8–12]
For these reasons, dihydropyridine compounds not only have attracted the
attention of chemists to synthesize but also represent an interesting research chal-
lenge. Numerous methods have been reported for the synthesis of 1,4-DHP deriva-
tives, because of the biological importance associated with these compounds.
The classical method involves the three-component coupling of an aldehyde with
b-ketoester and ammonia in acetic acid or in refluxing alcohol.[13,14] However, these
methods suffer from several drawbacks such as a long reaction time, an excess of
organic solvent, lower product yields, and harsh refluxing conditions. Therefore, it
is necessary to develop more efficient and versatile methods for the preparation of
1,4-DHPs, and the progress in this area is remarkable, including the use of micro-
waves,[15] ionic liquids,[16] refluxing at hight temperature,[17] TMSCl-NaI,[18] metal
triflates,[19] and I2.[20]
Also, other efficient methods for the synthesis of polyhydroquinoline deriva-
tives have been described, such as the recent use of microwaves,[21] heterogeneous
catalyst,[22] SiO2-HClO4,[23] silica gel–sulfonic acid,[24] tetrabutylammonium hydro-
gen sulfate,[25] ZnO,[26] ceric ammonium nitrate,[27] ZrCl4,[28] [2-MPyH]OTf,[29] gado-
linium triflate,[30] and solid-phase organic synthesis (SPOS) techniques.[31]
With a 1,4-DHP parent nucleus, acridine-1,8-diones have been developed
recently, as a family of efficient laser dyes[32] that are structurally similar to
NADH.[33] Acridinedione dyes have also been used as photoinitiators for polymer-
ization of acrylates and methyl acrylates[34] and photosensitizers for the onium salt
decomposition.[35] Many acridinediones have been synthesized by the reactions of
aldehydes with 2 equivalents of 1,3-dicarbonyl compounds via various methods.[36]
RESULTS AND DISCUSSION
As a continuation of our studies of multicomponent reactions,[37] we report in
this communication a novel and efficient synthesis of Hantzsch dihydropyridines by
a modified Hantzsch procedure (Scheme 1) using salicylic acid as catalyst under
different conditions.
Thus, the condensation of 1 equiv. of benzaldehyde 1a with 2 equiv. of ethyl
acetoacetate 2a and 4 equiv. of NH4OAc in the presence of 20 mol% of salicylic acid
resulted in the formation of Hantzsch 1,4-dihydropyridine 4a (Scheme 1). The
Scheme 1.

DIHYDROPYRIDINES AND ACRIDINEDIONES
961
Table 1. Salicylic acid–catalyzed Hantzsch synthesis of 1,4-dihydropyridine 4a under
different conditionsa
Entry
Solvent
Catalyst (mol %)
Temperature (ꢀC)
Time (h)
Yieldb (%)
1
2
3
4
5
6
EtOH
CH3CN
THF
—
20
20
20
20
10
5
Reflux
Reflux
Reflux
80
18
18
18
2
45
54
84
89
85
75
—
—
80
80
2
2
aAll reactions were performed using benzaldehyde (1 equiv.), ethyl acetoacetate (2 equiv.),
and ammonium acetate (4 equiv.).
b
Isolated yields.
reaction was performed in refluxed ethanol, and the product was isolated by the
usual workup in 45% yield only (Table 1, entry 1).
Several other solvents have been also used for this condensation, such as
CH3CN and tetrahydrofuran (THF). When the reaction was performed in CH3CN,
a moderate yield was obtained even with a prolonged reaction time, probably a result
of poor catalyst solubility, although the yield was comparable to that of EtOH. The
product yield was increased to 84% when THF was used (entry 3). However, the
reaction under solvent-free conditions gave better results within 2 h (Entry 4).
To optimize the reaction conditions further, the catalyst amount effect was
investigated with the optimum solvent, and the best result was obtained with
20 mol% of salicylic acid (entries 5 and 6).
Thus, the optimal reaction conditions for this transformation were determined
to be 20 mol% of the catalyst under solvent-free condition at 80 ꢀC.
With the optimized conditions in hand, the substrate scope of this reaction was
probed. In general, all the examined aldehydes could furnish the expected hetero-
cycles in good to excellent yields, and the results are summarized in Table 2. Changes
to the substituents seemed not to have any striking effect on the yield values.
All reactions were clean and efficient under solvent-free conditions, and the
products were obtained within 2 h in good yields.
Table 2. Salicylic acid–catalyzed Hantzsch synthesis of 1,4-dihydropyridines 4a–f under
optimized conditionsa
Entry
1,4-DHP
Ar
Time (h)
Yieldb (%)
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
C6H5-
4-OH-C6H4-
4-CH3O-C6H4-
4-Br-C6H4-
Styryl-
2
2
2
2
2
2
89
65
68
71
64
88
2-Furyl
aAll reactions were performed using aldehyde (1 equiv.), ethyl acetoacetate (2 equiv.),
ammonium acetate (4 equiv.), and salicylic acid (0.2 equiv.) at 80 ꢀC.
b
Isolated yields.

962
I. A. KHODJA ET AL.
Scheme 2.
Scheme 3.
A mechanism for the formation of compounds 4 is outlined in Scheme 3. The
Michael addition of 6a with enaminoester 7a, which are formed in situ from the
condensation reactions of ethyl acetoacetate 2a with aromatic aldehydes 1 and
ammonium acetate 3, respectively, give the intermediate 8a. Intramolecular cycload-
dition and subsequent dehydration afford compounds 4.
To study the generality of our methodology toward other 1,3-dicarbonyl
compounds, the synthesis of 9-aryl-3,3,6,6-tetramethyl-hexahydroacridine-
1,8-diones 5a–f was also explored. The reactions of different aldehydes 1 (1 equiv.)
with 5,5-dimethylcyclohexane-1,3-dione (dimedone) 2b (2 equiv.), ammonium acet-
ate (4 equiv.), and salicylic acid (0.2 equiv.) were performed under the optimized
solvent-free conditions to afford a series of the corresponding acridinediones
Table 3. Salicylic acid–catalyzed Hantzsch synthesis of acridinediones 5a–f under optimized conditionsa
Entry
Product
Ar
Time (h)
Yieldb (%)
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
C6H5-
3
5
3
5
3
3
82
67
73
85
88
90
2-CH3-C6H4-
4-CH3O-C6H4-
4-Cl-C6H4-
4-(CH3)2N-C6H4-
2-Thienyl
aAll reactions were performed using aldehyde (1 equiv.), dimedone (2 equiv.), ammonium acetate (4
equiv.), and salicylic acid (0.2 equiv.) at 80 ꢀC.
b
Isolated yields.

DIHYDROPYRIDINES AND ACRIDINEDIONES
963
(Scheme 2). The results summarized in Table 3 showed the high efficiency for the
one-pot multicomponent reaction.
All the products prepared from this method were characterized by their spec-
tral data and known compounds by comparison with reported data. The advantages
of the present protocols are the shorter reaction times and mild reaction conditions.
Because of the high reactivity of the reagents, the products are obtained in good
yields.
SUMMARY
In summary, we have found that salicylic acid is extremely useful and highly
efficient for the synthesis of 1,4-DHPs and acridinediones by means of
three-component condensations of an aldehyde, 1,3-dicarbonyl compound, and
ammonium nitrate in a one-pot condensation. This method is applicable to a wide
range of substrates, including aromatic, a, b-unsaturated, and heterocyclic alde-
hydes, and provides a variety of biologically relevant compounds in good yields
under solvent-free conditions. The mildness of the conversion, experimental sim-
plicity, compatibility with various functional groups, efficient yields, short reaction
times, and easy workup procedure make this procedure attractive for synthesizing
a variety of these derivatives.
EXPERIMENTAL
Typical Experimental Procedure for the Synthesis of 1,4-
Dihydropyridines 4a–f or Acridinediones 5a–f
A mixture of aldehyde (1 mmol), ammonium acetate (4 mmol), ethyl acetoace-
tate or dimedone (2 mmol), and salicylic acid (20 mol%) was magnetically stirred at
80 ꢀC under solvent-free conditions for the appropriate time indicated in Tables 2
and 3. After complete conversion as indicated by thin-layer chromatography
(TLC), the reaction mixture was cooled and poured onto crushed ice, and the sepa-
rated solid was filtered.
Diethyl 4-(Phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (4a)
Mp 156–158 ꢀC; lit.[38a] 158–160;1H NMR (250 MHz, CDCl3): d 1.25 (t,
J ¼ 7.1 Hz, 6H), 2.33 (s, 3H), 2.32 (s, 6H), 4.11 (q, J ¼ 7.1 Hz, 4H), 5.01 (s, 1H),
5.97 (s, 1H), 7.11–7.32 (m, 5H);13C NMR (62.9 MHz, CDCl3): d: 14.1, 19.5, 39.4,
59.3, 104.1, 127.5, 128.8, 135.7, 144.1, 145.9, 167.8; FT-IR (KBr): 3334, 1690,
1654, 1494, 1243, 1127, 721 cmꢁ1
.
9-(2-Methylphenyl)-3,3,6,6-tetramethyl-3,4,6,7,9,10-hexahydro-
1,8-(2H,5H)-acridinedione (5b)
Mp > 300 ꢀC;1H NMR (250 MHz, CDCl3): d: 1.20 (s, 6H, CH3), 1.34 (s, 6H),
2.32 (s, 3H), 2.38 (d, J ¼ 16.2 Hz, 2H), 2.44 (d, J ¼ 16.2 Hz, 2H), 2.51 (d, J ¼ 16.2 Hz,

964
I. A. KHODJA ET AL.
2H), 2.60 (d, J ¼ 16.2 Hz, 2H), 3.94 (s, 1H), 7.15–7.23 (m, 5H), 9.37 (s, 1H); 13C NMR
(62.9 MHz, CDCl3): d: 18.3, 26.7, 29.4, 32.3, 39.3, 40.2, 40.4, 50.7, 51.4, 114.3, 125.4,
128.0, 129.4, 135.9, 146.5, 148.7, 195.6; FT-IR (KBr): 3371, 3317, 3193, 2958, 1654,
1608, 1461, 1369, 1211, 1157 cmꢁ1. Anal. calcd. for C24H29NO2: C, 79.30; H, 8.04;
N, 3.85. Found: C, 79.45; H, 8.00; N, 3.84.
SUPPORTING INFORMATION
1
Full experimental detail and H and 13C NMR spectra can be found via the
‘‘Supplementary Content’’ section of this article’s Web page.
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