Synthesis of 9-aryl-3,4,6,7,9,10-hexahydroacridine-1,8(2Н,5Н)-diones

Article abstract of DOI:10.1134/S107036321701025X

The reaction in a mixture of 1,3-cyclohexanedione (dimedone), arylaldehyde, and ammonium acetate at 160°C during 10–15 min in the absence of solvent leads to the formation of 9-aryl-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-diones. The structure of the pr

Full text of DOI:10.1134/S107036321701025X

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 1, pp. 154–155. © Pleiades Publishing, Ltd., 2017.
Original Russian Text © O.E. Nasakin, M.I. Kazantseva, V.L. Gein, 2017, published in Zhurnal Obshchei Khimii, 2017, Vol. 87, No. 1, pp. 160–161.
LETTERS
TO THE EDITOR
Synthesis
of 9-Aryl-3,4,6,7,9,10-hexahydroacridine-1,8(2Н,5Н)-diones
O. E. Nasakina, M. I. Kazantsevaa, and V. L. Geinb*
a Chuvash State University, Cheboksary, Russia
b Perm State Pharmaceutical Academy, ul. Polevaya 2, Perm, 614000 Russia
*e-mail: geinvl48@mail.ru
Received August 25, 2016
Abstract—The reaction in a mixture of 1,3-cyclohexanedione (dimedone), arylaldehyde, and ammonium
acetate at 160°C during 10–15 min in the absence of solvent leads to the formation of 9-aryl-3,4,6,7,9,10-
1
hexahydroacridine-1,8(2H,5H)-diones. The structure of the products has been confirmed by IR and H NMR
spectroscopy data. Antimicrobial activity of the obtained compounds has been studied.
Keywords: 9-aryl-3,4,6,7,9,10-hexahydroacridine-1,8(2Н,5Н)-dione, Hantzsch synthesis, antimicrobial activity
DOI: 10.1134/S107036321701025X
Acridine and its analogs have been recognized for
antimicrobial activity [1]. Hantzsch reaction is used for
the preparation of 9,10-disubstituted decahydro-
acridine-1,8-diones [2]. This synthesis includes two
stages: the interaction of a cyclic 1,3-diketone with an
aldehyde affording Michael adduct and its
heterocyclization with a primary amine. A single-stage
preparation of such compounds via refluxing a mixture
of dimedone, an aldehyde, and a primary amine in
DMF medium in the presence of hydrochloric acid has
been suggested in [3]. This method of hexahydro-
acridine-1,8(2Н,5Н)-diones synthesis is simple, fast,
and gives the target product in a good yield.
during 10–15 min in the absence of solvent afforded 9-
aryl-3,4,6,7, 9,10-hexahydroacridine-1,8(2Н,5Н)-diones
1a–1e (Scheme 1).
Compounds 1a–1e were pale yellow crystalline
substances, soluble in DMF, DMSO, and ethanol (at
heating) and insoluble in water.
IR spectra of the prepared compounds contained the
bands of carbonyl group stretching vibrations (1640–
1648 cm–1), С=С bonds stretching vibrations (1596–
1612 cm–1), and heterocyclic N–H stretching vibra-
tions (3176–3192 cm–1). Besides the signals of aromatic
protons, a singlet of the Н9 proton (4.65–4.90 ppm),
1
and the NH proton signal (8.36–9.56 ppm), Н NMR
We found that keeping a mixture of 1,3-cyclohexane-
spectra of compounds 1d and 1e contained singlet
signals of protons of four methyl groups in positions 3
dione, arylaldehyde, and ammonium acetate at 160°С
Scheme 1.
R3
CHO
O
O
O
CH3COONH4
2
+
R1
R1
R1
O
N
R3
R2
R2
R2
H
1a_1e (78_81%)
R1 = R2 = H, R3 = Cl (а); R1 = R2 = H, R3 = MeО (b); R1 = R2 = H, R3 = 3-NO2 (c); R1 = R2 = CH3, R3 = МеО (d); R1 = R2 =
CH3, R3 = Cl (e).
154

SYNTHESIS OF 9-ARYL-3,4,6,7,9,10-HEXAHYDROACRIDINE-1,8(2Н,5Н)-DIONES
155
and 6 of the heterocycle (0.84–0.86, 1.03–1.05 ppm),
four doublets of protons at the С2, С7 and С4, С5 atoms
(1.96–2.40 ppm) with spin-spin coupling constant
16.5 Hz, and the spectra of compounds 1a–1c
contained multiplets of four protons at the С2 and С7
atoms (2.05–2.48 ppm), the С4 and С5 atoms (1.81–
2.25 ppm), С3 and С6 atoms (1.69–1.92 ppm). The
signals multiplicity was determined by the presence of
a chiral center in the position 9 of the molecules, making
the protons in positions 2, 4, 5, and 7 enantiotropic.
С2Н2, С7Н2), 1.87–1.96 m (4Н, С4Н2, С5Н2), 1.71–1.83
m (4Н, С3Н2, С6Н2), 4.90 s (1Н, С9Н), 7.20–7.92 m (4Н,
Ar), 9.54 s (1Н, NH). Found, %: С 67.45; Н 5.36; N 8.18.
С22Н14N2O4. Calculated, %: С 67.15; Н 5.53; N 7.98.
3,3,6,6-Tetramethyl-9-(4-methoxyphenyl)-
3,4,6,7,9,10-hexahydroacridine-1,8(2Н,5Н)-dione
(1d). Yield 2.95 g (78%), mp 273–275°С. IR spec-
trum, ν, cm–1: 1596 (С=C), 1644 (С=O), 3192 (NН).
1Н NMR spectrum, δ, ppm: 0.84 s and 1.052 s (12Н,
СН3), 1.96 d (2Н, С4Н2, J = 16.5 Hz), 2.11 d (2Н,
С5Н2, J = 16.5 Hz), 2.32 d (2Н, С2Н2, J = 16.5 Hz),
2.38 d (2Н, С7Н2, J = 16.5 Hz), 3.65 s (3Н, OCH3),
6.52–7.06 m (4Н, Ar), 8.36 s (1Н, NH). Found, %: С
75.96; Н 7.70; N 3.69. С24Н29NO3. Calculated, %: С
75.81; Н 7.89; N 3.85.
The spectral data showed that compounds 1a–1e
existed in the keto form with the proton localized at the
nitrogen atom.
Antimicrobial activity of compounds 1a–1e was
determined using a method of twofold serial dilution in
a liquid medium. Minimal suppressing concentrations
MSC (µg/mL) against the S. aureus АТСС 6538 and
E. coli ATCC 25922 strains [4] were determined. MSC
of the studied compounds was 1000 µg/mL, whereas
the MSC of a reference drug Dioxidine was 62.5–
1000 µg/mL against S. aureus АТСС 6538 and 3.9–
6.2 µg/mL against E. coli ATCC 25922. Hence, com-
pounds 1a–1e exhibited low antimicrobial activity.
3,3,6,6-Tetramethyl-9-(4-nitrophenyl)-3,4,6,7,9,10-
hexahydroacridine-1,8(2Н,5Н)-dione (1e). Yield
3.10 g (81%), mp >300°С. IR spectrum, ν, cm–1: 1596
(С=C), 1644 (С=O), 3192 (NН). 1Н NMR spectrum, δ,
ppm: 0.86 s and 1.042 s (12Н, СН3), 1.98 d (2Н, С4Н2,
J = 16.5 Hz), 2.08 d (2Н, С5Н2, J = 16.5 Hz), 2.29 d
(2Н, С2Н2, J = 16.5 Hz), 2.41 d (2Н, С7Н2, J = 16.5 Hz),
4.67 s (1Н, С9Н), 6.50–7.10 m (4Н, Ar), 8.41 s (1Н,
NH). Found, %: С 71.96; Н 6.83; N 3.65. С23Н26NO2Cl.
Calculated, %: С 71.72; Н 6.53; N 3.35.
1Н NMR spectra were recorded using a Bruker
DRX-500 instrument (500.13 MHz) in DMSO-d6 with
TMS as internal reference. IR spectra (KBr pellets)
were recorded using a Specord М-80 spectrophoto-
meter. Elemental analysis was performed using a Perkin
Elmer 2400 instrument. Melting points were determined
using a Melting Point M-565 instrument. The reaction
progress and the products purity were monitored by
means of TLC on Silufol UV-254 plates in a CHCl3–
AcOH (9 : 1) system developing with UV irradiation.
9-(4-Chlorophenyl)-3,4,6,7,9,10-hexahydroacridine-
1,8(2Н,5Н)-dione (1a). A mixture of 0.02 mol of 1,3-
cyclohexanedione, 0.01 mol of aromatic aldehyde, and
0.01 mol of ammonium acetate was kept during 10–
15 min at 150–160°С until gas evolution had ceased
and the reaction mixture became solid. After cooling,
the solid residue was treated with ethanol, filtered, and
recrystallized from ethanol. Yield 2.73 g (76%), mp
>300°С. IR spectrum, ν, cm–1: 1604 (С=С), 1644 (С=О),
1
3176 (NН). Н NMR spectrum, δ, ppm: 2.15–2.26 m
(4Н, С2Н2, С7Н2), 1.87–1.95 m (4Н, С4Н2, С5Н2), 1.75–
1.83 m (4Н, С3Н2, С6Н2), 4.82 s (1Н, С9Н), 6.92–7.36 m
(4Н, Ar), 9.36 s (1Н, NH). Found, %: С 69.62; Н 5.53; N
4.27. С22Н14NO2Cl. Calculated, %: С 69.52; Н 5.43; N 4.37.
ACKNOWLEDGMENTS
This work was financially supported by the Russian
Science Foundation (project no. 15-13-10029).
9-(4-Methoxyphenyl)-3,4,6,7,9,10-hexahydroacridine-
1,8(2Н,5Н)-dione (1b). Yield 2.77 g (78%), mp 273–
275°С. IR spectrum, ν, cm–1: 1612 (С=C), 1648 (С=O),
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3176 (NН). Н NMR spectrum, δ, ppm: 2.15–2.26 m
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9-(3-Nitrophenyl)-3,4,6,7,9,10-hexahydroacridine-
1,8(2Н,5Н)-dione (1c). Yield 2.97 g (80%), mp. >300°С.
IR spectrum, ν, cm–1: 1608 (С=C), 1640 (С=O), 3184
1
(NН). Н NMR spectrum, δ, ppm: 2.10–2.23 m (4Н,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 1 2017