Only acridine derivative from Hantzsch-type one-pot three-component reactions

Article abstract of DOI:10.1007/s00706-009-0211-x

A three-component Hantzsch-type condensation of different anilines with dimedone and benzaldehyde leads to the formation of a unique acridine derivative with an unusual breaking of a C-N bond. The reaction was also carried out employing rapid microwave or

Full text of DOI:10.1007/s00706-009-0211-x

Monatsh Chem (2009) 140:1529–1532
DOI 10.1007/s00706-009-0211-x
ORIGINAL PAPER
Only acridine derivative from Hantzsch-type one-pot
three-component reactions
•
Gisela C. Muscia Graciela Y. Buldain
•
´
Silvia E. Asıs
Received: 5 October 2009 / Accepted: 13 October 2009 / Published online: 4 November 2009
Ó Springer-Verlag 2009
Abstract A three-component Hantzsch-type condensa-
tion of different anilines with dimedone and benzaldehyde
leads to the formation of a unique acridine derivative with
an unusual breaking of a C–N bond. The reaction was also
carried out employing rapid microwave or conventional
heating and sonication as alternative energy sources, and
only this 1,8-dioxodecahydroacridine was obtained.
causative agents of Chagas disease, sleeping sickness, and
leishmaniasis, and resulted moderately cytotoxic [3]. Fur-
thermore, the National Cancer Institute (NCI, USA)
selected 2 (NSC747293) for in vitro one-dose testing
against 60 cell lines and it exhibited no growth inhibition.
Results and discussion
Keywords Multicomponent reactions ꢀ
Hantzsch-type condensation ꢀ Acridine derivatives ꢀ
N-unsubstituted acridinone
In the context of our ongoing research, we wished to pre-
pare other acridine derivatives from benzaldehyde, aniline,
and dimedone under solvent-free conditions. When the
reactants were exposed to microwave irradiation (MW) at
400 W for 8 min in equimolar amounts, no defined product
was observed. Surprisingly, when dimedone was in slight
excess (5–10%), a white solid product was obtained in 30%
yield. A ratio of 2:1 improved the yield of 3,4,6,7,9,10-
hexahydro-3,3,6,6-tetramethyl-9-phenylacridine-1,8(2H,5H)-
dione 3 up to 85% (Scheme 1). The structure of this
compound was established from its spectral data (1H NMR,
13C NMR, IR, and MS) and analytical data, which agreed
with the literature [4].
Introduction
Acridine derivatives have a wide spectrum of biological
activities as antibacterial, antimalarial, anticancer, and
mutagenic properties, principally connected with their
ability to inhibit the enzymes acting on nucleic acids [1].
In previous work, we reported a series of quinoline
derivatives as potential antiparasitic agents prepared via
¨
microwave-assisted Friedlander synthesis [2]. Among
them, the acridine derivative 1 was obtained employing
cyclohexanone as starting material. More recently, com-
pound 2 was synthesized according to Ref. [2] using 5,5-
dimethyl-1,3-cyclohexanedione (dimedone, Fig. 1). This
compound (TDR70446) showed no activity against the
The reported methods to obtain 3 and its analogues
employed ammonium hydroxide solution in 70% yield
[4], ammonium acetate and benzaldehydes with electron-
attracting groups [5], ammonium acetate with tris(penta-
fluorophenyl)borane catalysis [6], or the previously prepared
enaminone instead of aniline [7], as well as by catalytic
hydrogenation of the 3,3,6,6,-tetramethyloctahydroacridine-
1,8-dione derivative [8].
´
G. C. Muscia ꢀ G. Y. Buldain ꢀ S. E. Asıs (&)
´
Departamento de Quımica Organica,
Facultad de Farmacia y Bioquımica,
´
1,4-Dihydropyridines (DHPs) are well-known com-
pounds because of their pharmacological profile as calcium
channel modulators. Some methods are available in liter-
ature for the synthesis of acridine compounds containing an
1,4-DHP nucleus from dimedone, aldehyde, and different
´
Universidad de Buenos Aires,
´
Junın 956 (1113),
Ciudad de Buenos Aires, Argentina
e-mail: elizabet@ffyb.uba.ar
123

1530
G. M. Muscia et al.
More recently, compound 5 and several analogues were
prepared in good yields in CH3CN under reflux in the
presence of Amberlyst-15, an efficient heterogeneous cat-
alyst [11]. Moreover, they were also synthesized
employing an acidic IL [12].
N
N
Cl
Cl
Ph
1
Ph
2
O
Formation of 5 takes place through a Hantzsch-like
mechanism via conjugate addition of the enamine inter-
mediate 6 (obtained from dimedone and aniline) to the
Knoevenagel product 7 (obtained from dimedone and
benzaldehyde) followed by imino-enamino tautomerism
and subsequent ‘‘6-exo-trig’’ cyclization [10] (Scheme 3).
Herein, we assume a similar reaction mechanism which
somehow involves the breaking of the bond between car-
bon and nitrogen atoms concomitant with loss of water to
furnish the N-unsubstituted product. In order to support
this, we performed the same reaction employing 4-chlo-
roaniline, 4-methoxyaniline, and ammonium hydroxide,
respectively, under conventional heating. In all cases, 3
was the only product obtained in moderate to good yields.
Furthermore, we carried out the reaction from aniline,
benzaldehyde, and dimedone under conventional heating
Fig. 1 Structures of acridine derivatives 1 and 2
anilines or ammonium acetate via traditional heating in
organic solvent, under MW, and using ionic liquids (ILs) [9].
On the other hand, when anilines (or 1-naphthylamine)
and dimedone were used in 1:1 ratio, 9-aryl-3,4,9,10-tet-
rahydro-3,3-dimethylacridine-1(2H)-one 4 was obtained
[5, 9], meanwhile the ratio 1:2 provided 9,10-disubstituted-
decahydroacridine-1,8-diones 5 (Scheme 2).
The above-mentioned compounds are generally pre-
pared through a Hantzsch synthesis under a wide variety of
reaction conditions. Chebanov et al. [10] proposed that the
use of the high-boiling polar DMF as solvent appears
optimal to obtain the target compounds, without oxygen-
containing heterocycles contamination.
Scheme 1
NH2
CHO
O
O
Ph
O
neat
+
+
2
MW
400 W
N
H
O
3
Scheme 2
O
NH2
CHO
O
Ph
O
+
N
H
Ref. [6, 10]
O
4
Ref. [11,12]
2
O
O
Ph
O
N
Ph
5
123

Hantzsch-type one-pot three-component reactions
1531
Ph
NH2
N
CHO
O
O
O
PhHC
+
+
+
O
O
O
O
7
NHPh
6
O
Ph
Ph
O
O
O
O
O
Ph
O
- H2O
C-N
cleavage
N
O
NH
O
N
H
Ph
Ph
3
O
O
Ph
N
O
Ph
O
- H2O
N
OH
Ph
Ph
5
Scheme 3
(refluxing EtOH), MW (neat and EtOH solvent), and son-
ication (room-temperature EtOH), taking into account that
many different process parameters can be utilized to
modulate the selectivity, especially in multicomponent
reactions (MCRs) [13]. Again, 3 was the sole product
obtained in high yield, suggesting that the formation of this
compound is favored in all cases, independently of the
energy source.
discs. UV spectra were measured with a Jasco V-570 UV/
Vis/NIR spectrophotometer. Analytical TLC was per-
formed on DC-Alufolien Kieselgel 60 F254 Merck.
Microwave-assisted reactions were carried out in a Multi-
wave 3000 (Anton Paar GmbH). For reactions under
sonication, Testlab tb02 equipment was used.
7-Chloro-3,4-dihydro-3,3-dimethyl-9-phenylacridine-
1(2H)-one (2)
In summary, this work shows the formation of a unique
acridine derivative with an unusual breaking of a C–N
bond as a fundamental novelty, whatever the temperature,
reaction conditions, and anilines employed, leading to a
more stable product.
Compound 2 was prepared according to Ref. [2]. Reaction
time: 3 min (MW), white solid, m.p. 207–208 °C; yield
78%; 1H NMR (CDCl3): d = 8.06 (d, 1H, arom), 7.72 (dd,
1H, J = 9.20 Hz, J = 2.21 Hz), 7.54–7.69 (m, 3H, Ph),
7.49 (d, 1H, arom), 7.14–7.17 (m, 2H, Ph), 3.28 (s, 2H,
CH2), 2.57 (s, 2H, CH2), 1.24 (s, 6H, 2CH3) ppm; IR
-1
ꢀ
(KBr): m ¼ 3; 074; 1,757, 1,645, 1,277, 837, 754 cm
.
Experimental
3,4,6,7,9,10-Hexahydro-3,3,6,6-tetramethyl-9-phenylacri-
dine-1,8(2H,5H)-dione (3), typical procedure
Melting points were determined in a capillary Electro-
thermal 9100 SERIES-Digital apparatus. 1H and 13C NMR
spectra were recorded at rt using a Bruker 200 MHz
spectrometer with TMS as the internal standard. The
chemical shifts (d) are given in ppm. Infrared spectra were
recorded on a FT Perkin Elmer Spectrum One from KBr
A mixture of 0.98 g dimedone (7 mmol), benzaldehyde
(3.5 mmol), and aniline (3.5 mmol) was subjected to
microwave irradiation for 8 min at 400 W, 105 °C, and
18.3 bar. The reaction mixture was cooled and a white
solid precipitated. It was crystallized from EtOH to give a
123

1532
G. M. Muscia et al.
´
2. Muscia GC, Bollini M, Carnevale JP, Bruno AM, Asıs SE (2006)
Tetrahedron Lett 47:8811
3. Primary in vitro screening, Tropical Disease Research (TDR)
Program, World Health Organization (WHO), Switzerland
(http://www.tdr.org)
white solid powder, m.p. 195–197 °C, yield 63% (Ref. [5],
190–192 °C). The same reaction was performed employing
EtOH as solvent under MW (8 min, yield 85%) and also
with sonication at rt (30 min, yield 73%). It was also
carried out with conventional heating for 2 h in EtOH as
solvent and the yield was 49%. 1H NMR (200 MHz,
CDCl3): d = 11.80 (s, 1H, NH, exchanged D2O), 7.30–
7.09 (m, 5H, arom.), 5.54 (s, 1H, CH), 2.50–2.29 (m, 8H,
CH2), 1.24 (s, 6H, 2CH3), 1.11 (s, 6H, 2CH3) ppm; 13C
NMR (50 MHz, CDCl3): d = 190.42, 189.36, 138.06,
128.19, 126.77, 125.83, 115.58, 47.06, 32.74, 31.42,
´
4. Martın N, Quinteiro M, Seoane C, Soto JL (1995) J Heterocycl
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B, Jia R, Zhang J (2007) J Heterocycl Chem 44:83
6. Chandrasekhar S, Rao YS, Sreelakhshmi L, Mahipal B, Reddy
CR (2008) Synthesis 1737
7. Tu S, Jiang B, Zhang J, Jia R, Zhang Y, Yao C (2006) Org
Biomol Chem 4:3980
8. Stankevich EI, Vanags G (1965) Chem Abstr 63:6974 (Khim
Geterotsikl Soedin, Akad Nauk Latv SSR 1965 2:305)
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ꢀ
29.61, 27.40 ppm; IR (KBr): m ¼ 3; 430; 3,022, 2,963,
2,872, 1,600, 1,374, 1,248, 776, 694 cm-1. MS (EI):
m/z = 350 ([M ? 1]?), 241, 199, 83, 43.
Acknowledgments SANICO SRL Argentina and its personnel are
greatly acknowledged for providing the use of MW 3000 and tech-
nical help. We are grateful to Mr. Juan Pablo Carnevale for technical
assistance.
12. Dabiri M, Baghbanzadeh M, Arzroomchilar E (2008) Catal
Commun 939
13. Chebanov VA, Saraev VE, Desenko SM, Chernenko VN,
Knyazeva IV, Groth U, Glasnov TN, Kappe CO (2008) J Org
Chem 73:5110
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