One-pot, three-component reaction of dimedone, amines, and isatin in the presence of tris(hydrogensulfato) boron: Synthesis of pyrroloacridine derivatives

Article abstract of DOI:10.1007/s11164-014-1576-y

A one-pot, three-component reaction of dimedone, anilines. and isatin has been described leading to the synthesis of 2-arylpyrroloacridin-1(2H)-ones in the presence of tris(hydrogensulfato) boron [B(HSO₄)₃] at reflux in ethanol. However, in the cases of aliphatic amines, tetrahydroxanthene has been obtained from the reaction of isatin and dimedone.

Full text of DOI:10.1007/s11164-014-1576-y

Res Chem Intermed
DOI 10.1007/s11164-014-1576-y
One-pot, three-component reaction of dimedone,
amines, and isatin in the presence
of tris(hydrogensulfato) boron: synthesis
of pyrroloacridine derivatives
•
Zahed Karimi-Jaberi Alireza Jaafarizadeh
Received: 22 December 2013 / Accepted: 23 February 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract A one-pot, three-component reaction of dimedone, anilines. and isatin
has been described leading to the synthesis of 2-arylpyrroloacridin-1(2H)-ones in
the presence of tris(hydrogensulfato) boron [B(HSO4)3] at reflux in ethanol. How-
ever, in the cases of aliphatic amines, tetrahydroxanthene has been obtained from
the reaction of isatin and dimedone.
Keywords Pyrroloacridine Á Dimedone Á Anilines Á Isatin Á B(HSO4)3
Introduction
Heterocyclic compounds are a remarkably important class of compounds, making
up more than half of all known organic compounds. Heterocycles are present in a
wide variety of drugs, most vitamins, many natural products, biomolecules, and
biologically active compounds [1]. Thus, efforts to synthesize these compounds are
in demand by organic chemists.
Pyrroloacridone derivatives are of interest owing to their various pharmacolog-
ical and biological activities [2–4]. Acridine- and acridone-based compounds
comprise an important class of DNA-intercalating anticancer drugs [5]. A number of
acridine derivatives have exhibited interesting antitumor properties, including
acridone-4-carboxamide [6], and the bis-functionalized acridone/acridine-4-carbox-
amides [7].
Electronic supplementary material The online version of this article (doi:10.1007/s11164-014-1576-y)
contains supplementary material, which is available to authorized users.
Z. Karimi-Jaberi (&) Á A. Jaafarizadeh
Department of Chemistry, Firoozabad Branch, Islamic Azad University, P.O. Box 74715-117,
Firoozabad, Fars, Iran
e-mail: zahed.karimi@yahoo.com; z.karimi@iauf.ac.Ir
123

Z. Karimi-Jaberi, A. Jaafarizadeh
Thus, a variety of synthetic approaches are desirable to synthesize acridines from
dimedone, aldehydes, and aniline derivatives, or ammonium acetate via the Hantzch
reaction in the presence of various catalysts [8–13]. In this context, we planned to
employ isatin instead of an aldehyde. However, recently, Kefayati’s group reported
the reaction of dimedone, anilines, and isatinin in the ionic liquid [HMIm]HSO4 at
80 °C. This reaction afforded 2-arylpyrrolo[2,3,4-kl]acridin-1(2H)-ones [14]. Also,
these compounds were constructed by refluxing a mixture of isatins and enaminones
in toluene in the presence of an L-proline catalyst [15].
The B(HSO4)3 catalyst was prepared by the addition of chlorosulfonic acid to
boric acid at room temperature according to our reported method [16]. This
catalyst is safe and easy to handle and has been successfully applied for the
synthesis of biscoumarins [16], dihydroquinazolinones [17], and arylidenebisamide
derivatives [18].
Experimental
The B(HSO4)3 catalyst was prepared by addition of chlorosulfonic acid to boric acid
at room temperature according to our reported method [14].
General procedure for the synthesis of pyrroloacridine derivatives
A solution of dimedone (2 mmol), aniline (1 mmol), isatin (1 mmol), and B(HSO4)3
(0.10 g) in 5.0 mL ethanol (96 %) was stirred at reflux conditions for the
appropriate times (Table 1). Upon completion of the reaction, monitored by TLC,
the reaction mixture was allowed to cool to room temperature. The solid was filtered
off and washed with water (2 9 10 mL) and purified by recrystalization from
ethanol. The structures of all products 4a–f were confirmed by IR, 1HNMR,
13CNMR, and elemental analysis.
Compound (4a): IR (KBr): 3,035, 2,960, 1,698, 1,647, 1,460, 1,344, 1,095,
777 cm-1; 1H NMR (400 MHz, CDCl3): 1.34 (s, 6H, 2CH3), 3.23 (s, 2H, CH2), 5.64
(s, 1H, CH), 7.43 (t, J 6.4 Hz, 1H), 7.51–7.56 (m, 4H), 7.68 (t, J 6.8 Hz, 1H), 7.78
(t, J 7.6 Hz, 1H), 8.19 (d, J 8.0 Hz, 1H), 8.76 (d, J 8.0 Hz, 1H); 13CMNR
(100 MHz, CDCl3): 32.0, 38.2, 45.3, 119.5, 122.5, 123.8, 125.4, 126.1, 127.5,
127.6, 128.6, 128.9, 130.5, 130.6, 134,5, 135.9, 150.9, 155.7, 167.7.
Compound (4b): IR (KBr): 3,064, 2,957, 1,699, 1,649, 1,494, 1,346, 1,090, 830,
775 cm-1; 1HNMR (400 MHz, CDCl3): 1.34 (s, 6H, 2CH3), 3.23 (s, 2H, CH2), 5.62
(s, 1H), 7.47 (d, J 8.4 Hz, 2H), 7.53 (d, J 8.4 Hz, 2H), 7.69 (t, J 7.2 Hz, 1H), 7.77 (t,
J 7.8 Hz, 1H), 7.19 (d, J 8.4 Hz, 1H), 8.72 (d, J 8.4 Hz, 1H).
Compound (4d): IR (KBr): 3,045, 2,961, 1,703, 1,648, 1,491, 1,344, 1,116, 1,076,
821, 773 cm-1; 1HNMR (400 MHz, CDCl3): 1.34 (s, 6H, 2CH3), 3.23 (s, 2H, CH2),
5.63 (s, 1H), 7.41 (d, J 8.4 Hz, 2H), 7.67–7.69 (m, 3H), 7.78 (t, J 7.2 Hz, 1H), 8.18
(d, J 8.4 Hz, 1H), 8.71 (d, J 8.0 Hz, 1H).
Compound (5) IR (KBr): 3,332, 3,090, 2,960, 1,724, 1,693, 1,599, 1,377, 1,233,
1
1,129, 905 cm-1; HNMR (400 MHz, CDCl3): 1.08 (s, 6H, 2CH3), 1.13 (s, 6H,
123

One-pot, three-component reaction of dimedone, amines and isatin
R
NH2
O
O
O
O
B(HSO4)3
EtOH
N
O
N
H
R
N
1
2
3
4a-f
Scheme 1 Synthesis of pyrroloacridine derivatives
Table 1 Optimizing the reaction conditions for the synthesis of 4a
Entry
Catalyst (g)
Conditions
Time (min)
Yield (%)
1
2
3
4
5
6
–
Ethanol, r.t.
120
120
30
0
–
Ethanol, reflux
Ethanol, reflux
Ethanol, reflux
Ethanol, r.t.
Trace
50
96
0
B(HSO4)3, (0.05)
B(HSO4)3, (0.10)
B(HSO4)3, (0.10)
B(HSO4)3, (0.10)
5
120
30
Solvent-free, 100 °C
70
2CH3), 2.06–2.48 (m, 8H), 3.5 (s, 1H), 6.83 (d, J 6.8 Hz, 1H), 6.91–6.96 (m,
2H),7.20 (t, J 6.8 Hz, 1H).
Results and discussion
Our efforts to develop an efficient methodology for the synthesis of pyrroloacridine
derivatives focused initially on the three-component cyclocondensation of dime-
done with aniline and isatin as a model reaction (Scheme 1). Thus, a catalytic
amount of B(HSO4)3 was added to a mixture of dimedone, aniline, and isatin in
different solvents and under solvent-free conditions, and the reaction conditions
were optimized by conducting the reaction at different temperatures and employing
different loadings of the catalyst (Table 1). Pleasingly, we discovered that the
reaction was efficiently catalyzed by B(HSO4)3 at reflux conditions using ethanol as
a solvent, providing a high yield of product 4a (Table 1, Entry 4). A low yield of the
product was only obtained in the absence of the catalyst, indicating that the catalyst
was necessary to the reaction. The best result was obtained when the reaction was
conducted at reflux in ethanol in the presence of 0.10 g of the B(HSO4)3 catalyst.
The scope of this methodology was further extended by the reaction of various
anilines in this procedure. Different pyrroloacridine derivatives 4a–f were prepared
in short reaction times with good yields in the presence of B(HSO4)3(0.10 g). The
results are summarized in Table 2.
As shown in Table 2, anilines with halogen, methyl, and methoxy groups are
easily converted to their corresponding products under the same reaction conditions.
123

Z. Karimi-Jaberi, A. Jaafarizadeh
Table 2 One-pot synthesis of pyrroloacridone derivatives using B(HSO4)3 in ethanol
Entry
1
Amine
Product
Time (min)
5
Yield (%)
96
M.p. (°C)
193–194
NH2
O
N
N
4a
2
3
7
5
92
90
191–192
218–219
NH2
Cl
O
N
Cl
N
4b
NH2
Me
O
N
Me
N
4c
4
8
90
191–192
Br
NH2
O
N
Br
N
4d
4e
5
6
5
5
86
86
189–190
183–184
H3CO
NH2
O
N
OCH3
NH2
N
I
O
N
I
N
4f
However, when the reaction was triggered on anilines with electron-withdrawing
groups such as the nitro group, only a low yield of the product was obtained.
Furthermore, under the same conditions, it was observed that aliphatic amines,
such as methyl amine, 2-phenyl ethyl amine, and 1,2-ethylene diamine, failed to
react and tetrahydroxanthene 5 has been obtained from the reaction of isatin and
dimedone (Scheme 2).
The formation of the compounds 4 was assumed to proceed via formation of a
Michael adduct intermediate followed by cyclization according to Scheme 3. At
first, enamine 6 was derived in turn from condensation of dimedone and aniline.
123

One-pot, three-component reaction of dimedone, amines and isatin
O
O
NH
O
O
O
RNH2
O
N
O
H
O
3
1
5
R=CH3, PhCH2, H2N-(CH2)
Scheme 2 The reaction of isatin and dimedone in the presence of aliphatic amines
O
O
O
NH2
O
O
HO
H
O
NH
NH
N
H
B(HSO4)3
- H2O
- H2O
O
O
B(HSO4)3
N
O
N
NH
R
H
7
6
R
R
R
R
O
NH2
O
N
N
- H2O
O
O
N
N
N
4
8
R
R
Scheme 3 Proposed mechanism
Then, the reaction proceeds via formation of the intermediate 7, which is formed
in situ by reaction of isatin with the intermediate enamine 6. A proton shift from
intermediate 7 induces an intramolecular translactamization to give the intermediate
8. This intermediate undergoes a cyclocondenzation reaction to afford the
corresponding pyrroloacridine.
In conclusion, this article describes an efficient method for the synthesis of
pyrroloacridine derivatives through a one-pot three-component reaction of dime-
done, isatin, and anilines using B(HSO4)3 as catalyst under reflux in ethanol.
Moreover, aliphatic amines failed to react and tetrahydroxanthene has been
achieved from the reaction of isatin and dimedone. The present procedure offers
several unique advantages like high catalytic activity, short reaction times, good
yields, and simple workup.
123

Z. Karimi-Jaberi, A. Jaafarizadeh
Acknowledgment We gratefully acknowledge the funding support from Islamic Azad University,
Firoozabad Branch.
References
1. B. Eftekhari-Sis, M. Zirak, A. Akbari, Chem. Rev. 113, 2958 (2013)
2. E. Gimenez-Arnau, S. Missailidis, M.F.G. Stevens, Anti-Cancer Drug Res. 13, 431 (1998)
´
3. D. Tasdemir, K.M. Marshall, G.C. Mangalindan, G.P. Concepcion, L.R. Barrows, M.K. Harper, C.M.
Ireland, J. Org. Chem. 66, 3246 (2001)
4. L.A. McDonald, G.S. Eldredge, L.R. Barrows, C.M. Ireland, J. Med. Chem. 37, 3819 (1994)
5. A. Kamal, O. Srinivas, P. Ramulu, G. Ramesh, P.P. Kumar, Bioorg. Med. Chem. Lett. 14, 4107
(2004)
6. I. Antonini, P. Polucci, T.C. Jenkins, L.R. Kelland, E. Menta, N. Pescalli, B. Stefanska, J. Mazerski,
S. Martelli, J. Med. Chem. 40, 3749 (1997)
7. M.F. Brana, L. Casarrubios, G. Dominguez, C. Fernandez, J.M. Perez, A.G. Quiroga, C. Navarro-
Ranninger, B. Pascual-Teresa, Eur. J. Med. Chem. 37, 301 (2002)
8. V. Nadaraj, S.T. Selvi, S. Mohan, Eur. J. Med. Chem. 44, 976 (2009)
9. K. Niknam, F. Panahi, D. Saberi, M. Mohagheghnejad, J. Heterocycl. Chem. 47, 292 (2010)
10. S.T. Tu, Z. Lu, D. Shi, C. Yao, Y. Gao, C. Guo, Synth. Commun. 32, 2181 (2002)
11. A. Davoodnia, A. Zare-Bidaki, H. Behmadi, Chin. J. Catal. 33, 1797 (2012)
12. G.W. Wang, C.B. Miao, Green Chem. 8, 1080 (2006)
13. A. Javid, A. Khojastehnezhad, M. Heravi, F.F. Bamoharram, Synth. React. Inorg. Met-Org. Nan. 42,
14 (2012)
14. H. Kefayati, F. Narchin, K. Rad-Moghadam, Tetrahedron Lett. 53, 4573 (2012)
15. H. Wang, L. Li, W. Lin, P. Xu, Z. Huang, D. Shi, Org. Lett. 14, 4598 (2012)
16. Z. Karimi-Jaberi, M.R. Nazarifar, B. Pooladian, Chin. Chem. Lett. 23, 781 (2012)
17. Z. Karimi-Jaberi, L. Zarei, J. Chem. Res. 36, 194 (2012)
18. Z. Karimi-Jaberi, B. Pooladian, Monatsh. Chem. 144, 659 (2013)
123