An unexpected multicomponent reaction leading to 2-arylpyrrolo[2,3,4-kl] acridin-1(2H)-ones

Article abstract of DOI:10.1016/j.tetlet.2012.06.070

An unexpected condensation profile was observed for the three-component reaction of 5,5-dimethyl-1,3-cyclohexadione (dimedone), various anilines, and isatin leading to the synthesis of novel 2-arylpyrrolo[2,3,4-kl]acridin-1(2H)- ones in the ionic liquid [

Full text of DOI:10.1016/j.tetlet.2012.06.070

Tetrahedron Letters 53 (2012) 4573–4575
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Tetrahedron Letters
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An unexpected multicomponent reaction leading
to 2-arylpyrrolo[2,3,4-kl]acridin-1(2H)-ones
Hassan Kefayati a, , Fataneh Narchin b, Kurosh Rad-Moghadam c
⇑
a Department of Chemistry, Science and Research Branch, Islamic Azad University, PO Box 41635-4196, Guilan, Iran
b Department of Chemistry, Rasht Branch, Islamic Azad University, Rasht, Iran
c Department of Chemistry, Faculty of Sciences, University of Guilan, Rasht, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 19 June 2012
An unexpected condensation profile was observed for the three-component reaction of 5,5-dimethyl-1,3-
cyclohexadione (dimedone), various anilines, and isatin leading to the synthesis of novel 2-arylpyrrolo
[2,3,4-kl]acridin-1(2H)-ones in the ionic liquid [HMIm]HSO4. Regeneration of the enamine group after
the initial condensation reaction associated with participation of the restored amine group in translact-
onization with the pyrrolidone ring are suggested as the main differentiating events being favored over
addition of the second dimedone molecule, with respect to similar reported reactions.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reaction
Pyrroloacridine
Ionic liquid
Dimedone
Isatin
Pyrroloacridines and pyrroloacridones show a wide spectrum of
biological activities such as anthelmintic,1 antitumor,1,2 and anti-
fungal.3 Some of these compounds inhibit the growth of cancerous
cells via binding to DNA,4–6 whereupon they offer potential lead
frameworks for developing novel anticancer drugs. Only a few re-
ports7 are available on the synthesis of pyrroloacridines and the
majority of these compounds were found as the tetracyclic cores
in metabolites from marine sources such as plakinidines A–C and
alpkinidines.8 Herein, we describe a novel multicomponent reac-
tion providing an efficient approach to the synthesis of hitherto
unreported 2-arylpyrrolo[2,3,4-kl]acridin-1(2H)-ones.
There are numerous methods available in the literature which
describes reliable syntheses of acridines from dimedone, alde-
hydes, and aniline derivatives, or ammonium acetate via the
NH
O
O
O
N
NH2
O
O
[HMIm]HSO4
R
4
+
+
O
R
N
O
R
H
O
3
1
2
N
N
5
Scheme 1. The reaction leading to the synthesis of pyrroloacridones.
⇑
Corresponding author. Tel.: +98 131 7222822; fax: +98 131 7229629.
E-mail addresses: haskefayati@gmail.com, kefayati@iaurasht.ac.ir (H. Kefayati).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.070

4574
H. Kefayati et al. / Tetrahedron Letters 53 (2012) 4573–4575
fate, [HMIm]HSO4,16 at 80 °C, a powdery product was obtained
O
HO
O
with spectral data and elemental analysis inconsistent with the ex-
pected structure 4a (R = H). Indeed, the data were in good agree-
ment with the structure of an unprecedented product, 5a (R = H)
being assembled via ring-opening of isatin followed by formation
of a pyridine ring17 (Scheme 1).
O
O
NH2
O
H
NH
N
3
-H2O
H
O
+
O
N
NH
R
1
2
6
The mass spectrum of 5a showed a molecular ion peak at
m/z = 326, which was consistent with the mass of a 1:1:1 conden-
sation product of the three components having released three mol-
ecules of water. The 1H NMR spectrum of the product exhibited a
singlet integrating for six protons at d 1.35 corresponding to the
two methyl groups and clearly indicating that only one molecule
of dimedone had participated in the formation of the product 5a.
There were also two additional singlets in the spectrum at d 3.22
(2H) and 5.63 (1H) that were assigned to the resonances of the
methylene and olefinic methine protons, respectively. The aro-
matic region of the spectrum displayed separate signals for all
the aromatic protons at the expected chemical shifts and with
appropriate integral values. Further support for the structures of
compounds 5 was obtained from the 13C NMR spectra of the prod-
ucts where a downfield resonance (e.g., 166.7 for 5a) was apparent
corresponding to the presence of one carbonyl group in the
molecule. Based on these features the product was identified as
2-phenyl-4,5-dihydro-4,4-dimethylpyrrolo[2,3,4-kl]acridin-1(2H)-
one (5a).
R
R
H2N
O
O
O
NH
NH2
-H2O
O
O
O
N
N
N
H
8
7
R
N
R
R
R
O
-H2O
N
O
N
N
5
R
We have not established the exact mechanism for the formation
of pyrroloacridines 5, however, a reasonable suggestion is offered
in Scheme 2. It is thought that, the reaction proceeds via a cascade
of condensation reactions involving formation of the intermediate
7, which is formed in situ by reaction of isatin 3 with intermediate
enamine 6, derived in turn from condensation of dimedone and
aniline. Loss of a proton from intermediate 7 induces an intramo-
lecular translactamization (arrows on 7) to give the intermediate
8. This intermediate undergoes a cyclocondenzation reaction to af-
ford the corresponding 2-aryl-4,5-dihydro-4,4-dimethylpyrrol-
o[2,3,4-kl]acridin-1(2H)-one 5 (Scheme 2).
Optimization of the reaction conditions for the synthesis of 5a,
chosen as the model in [HMIm]HSO4 under conventional heating,
by exploring the effect of varying the temperature and amount of
reactants revealed that the best yield was obtained with two
equivalents of dimedone (Table 1).
Scheme 2. A proposed mechanism for the preparation of pyrroloacridones 5.
Table 1
Effect of temperature variation and amount of dimedone on the yield and time of the
model reaction
Entry
Dimedone (mmol)
T (°C)
Time (min)
Yield (%)
1
2
3
4
5
6
2
2
2
2
1.5
1
60
70
80
90
80
80
40
30
30
25
50
60
70
81
91
91
65
53
Hantzch reaction in the presence of various catalysts.9–14 In this
context, and in line with our interest in the synthesis of spiro-het-
erocyclic compounds,15 we planned to employ isatin instead of an
aldehyde in a similar reaction with dimedone (2 equiv) and aniline
(1 equiv) in order to produce spiro[oxindole-acridine] compounds.
However, when the reaction was conducted in the presence of the
Brønsted-acidic ionic liquid, 1-methylimidazolium hydrogensul-
The substrate scope of this protocol for the synthesis of a variety
of pyrrolo[2,3,4-kl]acridin-1(2H)-one derivatives was next studied
by applying various anilines to the reaction and, as shown in Table
2, aniline derivatives 2a–i, including those bearing electron-donat-
ing or electron-withdrawing as well as sterically demanding sub-
stituents, reacted efficiently with dimedone and isatin to afford
Table 2
Synthesis of pyrroloacridinones
Product
R
Method Aa
Method Bb
Mp (°C)
Time (min)
Yield (%)
Time (min)
Yield (%)
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
4-Cl
4-Br
4-I
4-NO2
3-Cl
4-OCH3
4-CH3
4-NO2, 2-CH3
30
35
35
35
45
35
25
25
50
91 (90,88,85)c
7
7
7
7
10
7
5
5
10
93 (91,90,88)c
196–197
189–190
191–192
204–205
181–182
179–180
185–186
220–221
185–186
88
88
90
83
86
92
90
85
91
90
90
86
89
95
92
89
Reaction conditions: dimedone (2 mmol), aniline (1 mmol), isatin (1 mmol), [HMIm]HSO4 (0.5 mL).
a
Conventional heating in an oil bath at 80 °C.
Sonication (45 KHz frequency) in a water bath at 80 °C.
The yields of reactions with recycled ionic liquid over three successive runs.
b
c

H. Kefayati et al. / Tetrahedron Letters 53 (2012) 4573–4575
4575
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We also examined the efficiency of the synthesis in terms of
yields and reaction times under ultrasound irradiation, likewise
at 80 °C in the ionic liquid [HMIm]HSO4. In all the cases studied,
the reaction proceeded smoothly to give better yields of products
5a–i in shorter times with respect to standard heating (Table 2).
The ionic liquid (IL) was easily separated from the reaction
medium by dissolving in distilled water, washing with diethyl
ether, and evaporation at 80 °C under reduced pressure for 1 h.
The recovered IL could be recycled in subsequent runs. Table 2
shows that no considerable change in the activity of the IL was ob-
served when it was reused over three successive runs.
In conclusion, we have developed a novel, efficient, and clean
route for the synthesis of a new class of pyrroloacridines via an
unexpected three-component reaction between dimedone, various
anilines, and isatin in the ionic liquid [HMIm]HSO4. The products
were successfully synthesized under classic reaction conditions
in the ionic liquid, and alternatively in higher yields and reduced
reaction times under ultrasound irradiation. The use of an inexpen-
sive and reusable ionic liquid, short reaction times, high yields,
simplicity of product isolation, and lack of problems connected
with conventional solvents are advantages of the procedure.
15. Kefayati, H.; Rad-Moghadam, K.; Zamani, M.; Hosseyni, S. Lett. Org. Chem. 2010,
7, 277–282.
Acknowledgment
16. For the preparation of 1-methylimidazolium hydrogen sulfate ([Hmim]HSO4),
see Hajipour, A. R.; Khazdooz, L.; Ruoho, A. E. Catal. Commun. 2008, 9, 89.
17. General procedure for the preparation of 2-aryl-4,5-dihydro-4,4-dimethylpyrrolo
[2,3,4-kl]acridin-1(2H)-ones 5a–i. Method A: Dimedone (0.28 g, 2 mmol),
aniline (1 mmol), and isatin (0.15 g, 1 mmol) were added to the ionic liquid
[HMIm]HSO4 (0.5 mL). The thoroughly stirred mixture was then heated in an
oil bath at 80ꢀC for the appropriate time according to Table 2. After completion
of the reaction, as indicated by TLC, the mixture was allowed to cool to room
temperature and then H2O (5 mL) was added. The obtained precipitate was
filtered and the crude product recrystallized from EtOH (96%). Method B: A
mixture of dimedone (2 mmol), aniline (1 mmol), isatin (1 mmol), and
[HMIm]HSO4 (0.5 mL) was sonicated (45 KHz frequency) in a H2O bath at 80
ꢀC for the appropriate time according to Table 2. After completion of the
reaction, H2O (5 mL) was added. The obtained precipitate was filtered and
crystallized from EtOH (96%).
Financial support by the Islamic Azad University, Rasht Branch
is gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
06.070.
References and notes
2-Phenyl-4,5-dihydro-4,4-dimethylpyrrolo[2,3,4-kl]acridin-1(2H)-one (5a):
Pale yellow powder, Mp 196–197 °C, IR (KBr): 3035, 2960, 1704, 1647, 1488,
1. Inman, W. D.; O’Neill-Johnson, M.; Crews, P. J. Am. Chem. Soc. 1990, 112, 1–4.
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1342, 1115, 1074, 819, 775 cmÀ1 1H NMR (400 MHz, CDCl3): dH 1.35 (s, 6H, 2
;
CH3), 3.22 (s, 2H, CH2), 5.63 (s, 1H), 7.32 (t, J 6.4 Hz, 1H), 7.51–7.59 (m, 4H),
7.65 (t, J 6.8 Hz, 1H), 7.78 (t, J 7.6 Hz, 1H), 8.20 (d, J 8.0 Hz, 1H), 8.75 (d, J 8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3): dC 30.8, 37.1, 44.19, 118.3, 122.6, 124.2, 124.9,
126.3, 126.4, 127.4, 127.8, 129.3, 129.4, 129.5, 133.3, 134.7, 149.7, 154.5,
166.7; MS: m/z (%) = 327 (M+1, 7), 326 (M, 32), 311 (100), 296 (15), 268 (18),
192 (10), 167 (48), 149 (88), 77 (16); Anal. Calcd for C22H18N2O: C, 80.96; H,
5.56; N, 8.58. Found: C, 80.91; H, 5.58; N, 8.65.