An efficient synthesis of pyrrolo[2,3,4-kl]acridin-1-one derivatives catalyzed by L-proline

Article abstract of DOI:10.1021/ol302058g

An efficient domino approach for the synthesis of novel pyrrolo[2,3,4-kl]acridin-1-one derivatives has been established. This reaction represents the first facile conversion of an isatin to a pyrrolo[2,3,4-kl] acridin-1-one via a C-N bond cleavage reaction without the need for a multistep reaction process.

Full text of DOI:10.1021/ol302058g

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
An Efficient Synthesis of
Pyrrolo[2,3,4-kl]acridin-1-one
Derivatives Catalyzed by L‑Proline
Huiyuan Wang, Lili Li, Wei Lin, Pan Xu, Zhibin Huang,* and Daqing Shi*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123,
P. R. China
zbhuang@suda.edu.cn; dqshi@suda.edu.cn
Received July 25, 2012
ABSTRACT
An efficient domino approach for the synthesis of novel pyrrolo[2,3,4-kl]acridin-1-one derivatives has been established. This reaction represents
the first facile conversion of an isatin to a pyrrolo[2,3,4-kl]acridin-1-one via a CÀN bond cleavage reaction without the need for a multistep reaction
process.
Functionalized heterocyclic building blocks are of great
importance to both medicinal and organic chemists, and
their synthesis continues to represent a challenge from
both an academic and industrial perspective.1 The acridine
derivatives are an important class of heterocyclic pharma-
ceuticals and bioactive natural products because of their
significant and wide spectrum of biological activities.
Acridine derivatives display a broad range of biological
properties including antiparasitic,2 antibacterial,3 and
antitumor activity.4
possess a unique heterocyclic pyrrolo[2,3,4-kl]acridine par-
ent ring system (Figure 1). Although there have been many
studies on the synthesis of these molecules,6,7 these methods
require multistep syntheses. Thus, there is a need for the
development of concise and efficient methods for the con-
struction of this heterocyclic skeleton and its analogues.
Nowadays, the development of concise and effective one-
pot transformations for the construction of target compound
libraries represents a major challenge in organic synthesis.8 A
number of strategies have been developed to overcome this
In 1990, three novel pentacyclic alkaloids, Plakinidines
A, B, and C (Figure 1), were isolated from a Plakortis
sponge.5 Plakinidines A and B exhibited in vitro activity
against Nippostrongylus brastiliensis, and Plakinidine A
showed activity against reverse transcriptase. These alkaloids
(1) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc.
Chem. Res. 2008, 41, 40.
(2) Guetzoyan, L.; Ramiandrasoa, F.; Dorizon, H.; Desprez, C.;
Bridoux, A.; Rogier, C.; Pradines, B.; Perree-Fauvet, M. Bioorg. Med.
Chem. 2007, 15, 3278.
(3) (a) Wainwright, M. J. Antimicrob. Chemother. 2001, 47, 1. (b)
Mylari, B. L.; Lombardino, J. G.; McManus, J. M. U.S. Patent
5,624,929, 1997.
Figure 1. Structures of pyrrolo[2,3,4-kl]acridine derivatives and
the targeted skeleton.
(4) (a) Denny, W. Curr. Med. Chem. 2002, 9, 1655. (b) Koller, A.;
Rudi, A.; Garcia, M.; Kashman, Y. Molecules 2001, 6, 300.
(5) (a) Inman, W. D.; O’Neill-Johnson, M.; Crews, P. J. Am. Chem.
Soc. 1990, 112, 1. (b) West, R. R.; Mayne, C. L.; Ireland, C. M.; Brinen,
L. S.; Clardy, J. Tetrahedron Lett. 1990, 31, 3271.
(6) Gellerman, G.; Rudi, A.; Kashman, Y. Tetrahedron 1994, 50,
12959.
r
10.1021/ol302058g
XXXX American Chemical Society

challenge, and the domino reaction in particular has
received considerable attention. Reactions of this type
offer a wide range of possibilities for the efficient con-
struction of highly complex molecules in a single process
consisting of several steps, thus avoiding the require-
ment for complicated purification stages and therefore
allowing for considerable savings in the use of both
solvents and reagents. For these reasons, the domino
reaction has been used as a tool for delivering high levels
of diversity in targeted compound libraries.9
Small organic molecules such as the cinchona alkaloids,
L-proline, and their derivatives are readily available com-
mercial catalysts and have been used in various transfor-
mations with excellent yields.10 For example, L-proline
has been used in enamine-based direct catalytic asym-
metric Aldol,11 Mannich,12 Michael,13 DielsÀAlder,14 R-
amination,15 and Knoevenagel type reactions,16 as well as
an unsymmetric Biginelli reaction.17 Recently, L-proline
and its derivatives have been used in domino reactions;18
we also reported the synthesis of a series of heterocycles
using domino reactions catalyzed by L-proline.19 In the
current paper, we report a novel domino reaction for the
synthesis of pyrrolo[2,3,4-kl]acridine derivatives using
L-proline as the catalyst. The attractive features of the
current domino reaction include the novel construction of
the pyrrolo[2,3,4-kl]acridine skeleton and the direct CÀN
Table 1. Optimizing the Reaction Conditions for the Synthesis
of 3a
catalyst
(mol %)
t
yielda
(%)
entry
solvent
ethanol
(°C)
1
;
reflux
reflux
reflux
reflux
reflux
reflux
80
trace
23
2
ethanol
acetonitrile
chloroform
THF
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
piperidine (10)
phenylalanine (10)
L-proline (5)
3
22
4
52
5
33
6
1,4-dioxane
DMF
20
7
40
8
water
80
trace
82
9
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
80
10
11
12
13
14
15
16
17
18
80
57
80
49
80
80
L-proline (15)
L-proline (20)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
80
74
80
70
40
11
60
20
100
reflux
84
90
(7) Kitahara, Y.; Mizuno, T.; Kubo, A. Tetrahedron 2004, 60, 4283.
(8) Wang, F.; Liu, H, X.; Fu, H.; Jiang, Y. Y.; Zhao, Y. F. Org. Lett.
2009, 11, 2469.
a Yield was determined by HPLC-MS.
(9) (a) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, 2006. (b) Tietze, L. F.; Brazel,
C. C.; Holsken, S.; Magull, J.; Ringe, A. Angew. Chem., Int. Ed. 2008, 47,
5246. (c) Trost, B. M. Science 1991, 254, 1471. (d) Padwa, A. Chem. Soc.
Rev. 2009, 38, 3072. (e) Padwa, A.; Bur, S. K. Tetrahedron 2007, 63, 5341.
(f) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2005, 127, 15051. (g) Lu, M.; Zhu, D.; Lu, Y.; Hou, Y.; Tan,
B.; Zhong, G. Angew. Chem., Int. Ed. 2008, 47, 10187.
(10) (a) Chandrasekhar, S.; Reddy, N. R.; Sultana, S. S.; Narsihmulu,
C.; Reddy, K. V. Tetrahedron 2006, 62, 338. (b) Li, H.; Wang, B.; Deng, L.
J. Am. Chem. Soc. 2006, 128, 732.
(11) Alcaide, B.; Almendros, P.; Luna, A.; Torres, M. R. J. Org.
Chem. 2006, 71, 4818.
(12) (a) Janey, J. M.; Hsiao, Y.; Armstrong, J. D., III. J. Org. Chem.
2006, 71, 390. (b) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am.
Chem. Soc. 2002, 124, 827.
(13) (a) Rasalkar, M. S.; Potdar, M. K.; Mohile, S. S.; Salunkhe,
M. M. J. Mol. Catal. A: Chem. 2005, 235, 267. (b) Kotrusz, P.; Toma, S.
Molecules 2006, 11, 197. (c) Kotrusz, P.; Toma, S. ARKIVOC 2006, 100.
(14) Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III. Angew.
Chem. 2003, 115, 4365.
(15) Bogevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.;
Jorgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790.
(16) Hossein, A. O.; Elham, R.; Majid, M. H. J. Chem. Res. 2006,
246.
(17) (a) Yadav, J. S.; Kumar, S. P.; Kondaji, G.; Rao, R. S.; Nagaiah,
K. Chem. Lett. 2004, 33, 1168. (b) Mabry, J.; Ganem, B. Tetrahedron
Lett. 2006, 47, 55.
(18) (a) Kumar, A.; Maurya, R. A. Tetrahedron 2007, 63, 1946.
(b) Indumathi, S.; Perumal, S.; Menendez, J. C. Tetrahedron 2011, 67,
7101. (c) Guo, S. B.; Wang, S. X.; Li, J. T. Synth. Commun. 2007, 37,
2111. (d) Jiang, H. F.; Mai, R. H.; Gao, H.; Zhu, Q. H.; Liu, X. H. Org.
Biomol. Chem. 2009, 7, 4943. (e) Jiang, H. F.; Li, J. H.; Chen, Z. W.
Tetrahedron 2010, 66, 9721.
bond cleavage of an isatin, both of which were easily
achieved without the need for multistep operations.
We initially evaluated the domino reaction of the en-
aminone 1a, which was derived from the reaction of aniline
with 5,5-dimethylcyclohexane-1,3-dione, and isatin 2a.
The reaction mixture, which was composed of a 1:1
mixture of 1a to 2a, was tested under a variety of different
conditions. The results are summarized in Table 1.
The optimization process revealed that the reaction
could not proceedinethanol under catalyst-free conditions
(Table 1, entry 1). Pleasingly, when the reaction was
conducted in the presence of L-proline (10 mol %) in
ethanol, the target compound 3a was obtained in 23%
yield (Table 1, entry 2). To improve the yield, different
solvents were evaluated. The results indicated that toluene
provided much better results than ethanol, acetonitrile,
chloroform, tetrahydrofuran (THF), 1,4-dioxane, N,N-
dimethylformamide (DMF), and water (Table 1, entries
2À9). Several other organocatalysts were also evaluated
for their catalytic efficiency in the current reaction. In all
cases, 10 mol % of the catalyst was used and the reaction
was carried out in toluene at 80 °C. The results revealed
that L-proline provided a superior catalytic effect to piper-
idine and phenylalanine (Table 1, entries 10À11). These
results indicated that the presence of both secondary
nitrogen and carboxylic acid groups may be essential for
better catalytic activity.
(19) (a) Shi, C. L.; Shi, D. Q.; Kim., S. H.; Huang, Z. B.; Ji, M. Aust.
J. Chem. 2008, 61, 547. (b) Shi, C. L.; Chen, H.; Shi, D. Q. J. Heterocycl.
Chem. 2011, 48, 351. (c) Shi, C. L.; Chen, H.; Shi, D. Q. J. Heterocycl.
Chem. 2012, 49, 125. (d) Shi, C. L.; Wang, J. X.; Chen, H.; Shi, D. Q.
J. Comb. Chem. 2010, 12, 430. (e) Li, Y. L.; Chen, H.; Shi, C. L.; Shi,
D. Q.; Ji, S. J. J. Comb. Chem. 2010, 12, 231.
B
Org. Lett., Vol. XX, No. XX, XXXX

Having identified L-proline as the best organocatalyst
for the transformation, we proceeded to evaluate the
amount of L-proline required for this reaction. The results
revealed that increasing the amount of L-proline from 5
to 10 mol % led to an increase in the yield from 80% to
82% (Table 1, entries 12 and 9). The use of 10 mol % of
L-proline in toluene was effective in pushing this reaction
forward, and the addition of larger amounts of the
catalyst did not improve the yields. To identify the
optimum reaction temperature, the reaction was carried
out with 10 mol % L-proline at 40, 60, 80, and 100 °C and
reflux temperature, providing the product 3a in yields of
11%, 20%, 82%, 84%, and 90% (Table 1, entries 15À18
and 9), respectively. Thus, the optimum conditions re-
quired the use of 10 mol % L-proline in a toluene solvent
at reflux.
groups on the enaminone ring, were well tolerated under the
reaction conditions, leading to the final products in satis-
factory yields (up to 93%). Under the standard condi-
tions, 4-chloroisatin (Table 2, 3y) remained intact and
only the starting materials were recovered. This failure to
react was attributed to the effect of steric hindrance upon the
reactivity of the carbonyl group.
To expand the scope of the current method, N-substituted
3-aminocyclohex-2-enone (4) was examined as a replace-
ment for the N-substituted 3-amino-5,5-dimethylcyclohex-
2-enone (1). Surprisingly, the desired 4,5-dihydropyrrolo-
[2,3,4-kl]acridine derivatives 3 were not obtained under
the optimized conditions and the corresponding oxida-
tion products pyrrolo[2,3,4-kl]acridine derivatives 5 were
obtained instead in good yields (Table 3). The reaction
With the optimal conditions in hand (toluene, reflux,
10 mol % L-proline), we proceeded to investigate the sub-
strate scope of the transformation. As shown in Table 2,
methyl, bromo, chloro, and fluoro substituents on the isatin
ring, and n-butyl, naphthalene-1-yl, and phenyl groups
bearing either electron-withdrawing or electron-donating
Table 3. Preparation of Compounds 5
time
(h)
yielda
(%)
Table 2. Preparation of Compounds 3
product
R1
R2
5-F
5a
5b
5c
5d
5e
5f
2,4-(CH3)2C6H3
2,4-(CH3)2C6H3
2,4-(CH3)2C6H3
4-CH3OC6H4
n-C4H9
2
80
84
78
78
80
60
82
79
81
80
82
76
76
H
2
6-Cl
7-CF3
5-CH3
H
2
2
1.5
3
4-NO2C6H4
C6H5
time
(h)
yielda
(%)
5g
5h
5i
5-Cl
5-Br
H
2.5
2.5
2.5
2
product
R1
R2
C6H5
C6H5
3a
3b
3c
3d
3e
3f
C6H5
C6H5
C6H5
C6H5
H
2
90
92
87
89
93
82
90
87
89
90
84
91
90
85
80
82
78
78
92
90
80
90
90
90
NR
5j
4-CH3C6H4
naphthalene-1-yl
naphthalene-1-yl
2-ClC6H4
5-Cl
H
5-F
2
5k
5l
1.5
1.5
2
6-Cl
5-Br
5-Br
6-Br
H
2
5-Br
5-F
1.5
2
5m
4-BrC6H4
4-BrC6H4
2
a Yield was isolated yield.
3g
3h
3i
4-BrC6H4
2.5
2
4-BrC6H4
6-Cl
5-CH3
5-F
4-BrC6H4
2
pathways could therefore been controlled by varying the
enaminones with a different substituted pattern to give a
series of novel 4,5-dihydropyrrolo[2,3,4-kl]acridin-1-ones and
pyrrolo[2,3,4-kl]acridin-1-ones selectively.
The structures of the products were identified from their
IR, 1H NMR, 13C NMR, and HRMS spectra. The struc-
tures of compounds 3b and 5m were further confirmed by
X-ray analysis (Figures 2 and 3).
In accordance with reports from the literature,20 we
have proposed a mechanism for the current L-proline-
catalyzed domino reaction (Scheme 1). The initial nucleo-
philic reaction of L-proline on the isatin affords inter-
mediate 6, which is subsequently attacked by enaminone
to give intermediate 7. Intermediate 7 undergoes imine-
enamine tautomerization to give intermediate 8, which sub-
sequently reacts in an intramolecular cyclization and ring-
opening sequence to give compound 10. Intramolecular
3j
4-BrC6H4
2
3k
3l
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
3-Cl-4-FC6H3
3-Cl-4-FC6H3
3-Cl-4-FC6H3
n-C4H9
5-Cl
6-Br
5-Br
H
3
2
3m
3n
3o
3p
3q
3r
3s
3t
3
2.5
4.5
4.5
4
6-Cl
5-Cl
5-F
H
4
5-Br
H
2.5
2.5
2.5
2.5
2
3u
3v
3w
3x
3y
5-Cl
H
n-C4H9
6-Br
5-Br
4-Cl
naphthalene-1-yl
C6H5
3
4.5
a Yield was isolated yield.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 1. Proposed Mechanism of the Domino Reaction
Figure 2. Molecular structure of compound 3b.
Figure 3. Molecular structure of compound 5m.
imine formation then leads to the formation of inter-
mediate 12, which loses the molecule L-proline to give
the desired product 3. When R is H in compound 3, the
product 3 would be oxidized by oxygen in the air to give
product 5.
In conclusion, we have developed a procedure for the
facile synthesis of a variety of potentially biologically active
pyrrolo[2,3,4-kl]acridines based on a novel domino reac-
tion. Using this method, a diverse collection of pyrrolo-
[2,3,4-kl]acridine derivatives was rapidly constructed with
excellent yields by simply refluxing a mixture of isatins and
enaminones in toluene in the presence of an L-proline
catalyst.
Acknowledgment. We are grateful for financial support
from the Major Basic Research Project of the Natural Science
Foundation of the Jiangsu Higher Education Institutions
(No. 10KJA150049), a project fund from the Priority Aca-
demic Project Development of the Jiangsu Higher Education
Institutions and the Foundation of the Key Laboratory of
Organic Synthesis of the Jiangsu Province (No. JSK0812).
Supporting Information Available. Experimental proce-
dures, spectroscopic data for all compounds 3 and 5, and
crystal data for compounds 3b and 5m. This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) (a) Shi, C. L.; Shi, D. Q.; Kim, S. H.; Huang, Z. B.; Ji, S. J.; Ji, M.
Tetrahedron 2008, 64, 2425. (b) Yu, F.; Yan, S.; Hu, L.; Wang, Y.; Lin, J.
Org. Lett. 2011, 13, 4782.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX