A domino synthetic strategy leading to two-carbon-tethered fused acridine/indole pairs and fused acridine derivatives

Article abstract of DOI:10.1039/c2ob26315g

A series of new poly-functionalized two-carbon-tethered fused acridine/indole pairs were synthesized via Bronsted acid-promoted domino reactions between indoline-2,3-dione and C₂-tethered indol-3-yl enaminones. The reactions were further expanded to prepare C-tethered fused acridine/pyridine pairs, N-substituted amino acids, N-cyclopropyl and N-aryl substituted fused acridine derivatives, as well as bis-furan-3-yl-substituted indoles. During these reaction processes, the domino construction of a fused acridine skeleton with concomitant formation of two new rings was readily achieved in a one-pot operation. The procedures are facile, avoiding time-consuming and costly syntheses, tedious work-up and purification of precursors.

Full text of DOI:10.1039/c2ob26315g

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 8533
www.rsc.org/obc
PAPER
A domino synthetic strategy leading to two-carbon-tethered fused
acridine/indole pairs and fused acridine derivatives†
Bo Jiang,* Xue Wang, Meng-Yuan Li, Qiong Wu, Qin Ye, Hai-Wei Xu and Shu-Jiang Tu*
Received 10th July 2012, Accepted 6th September 2012
DOI: 10.1039/c2ob26315g
A series of new poly-functionalized two-carbon-tethered fused acridine/indole pairs were synthesized via
Brønsted acid-promoted domino reactions between indoline-2,3-dione and C2-tethered indol-3-yl
enaminones. The reactions were further expanded to prepare C-tethered fused acridine/pyridine pairs,
N-substituted amino acids, N-cyclopropyl and N-aryl substituted fused acridine derivatives, as well as
bis-furan-3-yl-substituted indoles. During these reaction processes, the domino construction of a fused
acridine skeleton with concomitant formation of two new rings was readily achieved in a one-pot
operation. The procedures are facile, avoiding time-consuming and costly syntheses, tedious work-up and
purification of precursors.
of enormous efforts aimed at understanding the rules for control-
Introduction
ling the efficiency and selectivity of the starting materials
cascade responsible for multi-ring construction. The domino
reactions for use in the total synthesis of natural products or
natural-like structures were one of the key tools that enabled the
multi-ring-junction frameworks to be predicted by controlling
the reaction process.12,13 They also form an ideal platform for
rapid generation of both complexity and diversity in a collection
of compounds with predefined functionality, e.g. ligands for cat-
alysis or bioactive compounds. Very recently, we have developed
a series of new domino reactions that provided easy access to
multiply functionalized ring structures of chemical and pharma-
ceutical interest.14,15 In the course of our continuous efforts on
the development of useful domino reactions herein, we would
like to report another new synthetic strategy for the efficient
preparation of polyfunctionalized heterocycles containing fused
acridine and indole skeletons through intermolecular domino
reactions. This reaction was achieved from the available starting
materials such as indoline-2,3-dione and C2-tethered indol-3-yl
enaminones in HOAc under microwave heating conditions
(Scheme 1). The great aspect of the present domino reaction is
shown by the fact that the synthesis of new polyfunctionalized
heterocycles containing fused acridines/indole units connected
through a sp3–C2 bridge was readily achieved via a Brønsted
acid-promoted domino reaction in a single step, and two new
Heterocyclic compounds embedded with nitrogen are prevalent
in numerous natural products and pharmaceutical leads. Among
the nitrogen heterocycles, the partially fused acridine derivatives
are important motifs, displaying remarkable pharmaceutical or
biochemical activities,1 such as antitumor2 and antifungal.3 On
the other hand, the indole moiety has been found in various
pharmacologically and biologically active compounds.4 Many
indole alkaloids are recognized as one of the rapidly growing
groups of marine invertebrate metabolites for their broad spec-
trum of biological properties,5 such as anticancer, anti-tumour,6
anti-inflammatory, hypoglycemic, analgesic and anti-pyretic
activities.7 Thus, an assembly of these two motifs could poten-
tially lead to a series of structurally and biologically interesting
compounds. Although the synthesis and application of fused
acridines1 and indole8,9 derivatives have been reported, respecti-
vely, in the literature, to the best of our knowledge the direct syn-
thesis of two-carbon-tethered fused acridine/indole pairs has
been not achieved so far.
Creation of complex polycyclic skeletons of chemical and bio-
medical importance from simple and readily available precur-
sors, while combining economic and environmental aspects,
stands as one of the crowning achievements in organic chemi-
stry.10,11 The state of the art synthetic strategy reflects the sum
School of Chemistry and Chemical Engineering, Jiangsu Key
Laboratory of Green Synthetic Chemistry for Functional Materials,
Jiangsu Normal University, Xuzhou, Jiangsu, P. R. China.
E-mail: jiangchem@jsnu.edu.cn, laotu@jsnu.edu.cn;
Fax: +86 51683500065; Tel: +86 51683500065
†Electronic supplementary information (ESI) available. CCDC reference
numbers 891836, 891837. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2ob26315g
Scheme 1 The synthesis of fused acridine/indole pairs 3.
Org. Biomol. Chem., 2012, 10, 8533–8538 | 8533
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 1 Optimization of the catalyst in the synthesis of 4a under MW
rings including pyrrole and pyridine frameworks were readily
constructed in an intermolecular domino manner and in a one-
pot operation.
Entry
Solvent
T (°C)
Time (min)
Yielda (%)
1
2
3
4
5
6
7
8
DMF
EtOH
Toluene
HOAc
HOAc
EtCOOH
HCOOH
CF3COOH
90
90
90
90
110
90
90
90
20
20
20
20
20
20
20
20
Trace
Trace
Trace
78
84
38
Results and discussion
The chemistry of enaminones possessing 1,3-bisnucleophilic
centers has numerous attractive features that have made them
important building blocks in current organic trends. They have
gained considerable prominence due to their use in the treatment
of epilepsy and because they possess a variety of other medicinal
properties.16 Over the decades, enaminones have been used for
the synthesis of a wide variety of heterocyclic compounds.15a,
64
45
a Isolated yield.
b,17
pairs 3g–3j in 70%–82% yields (Scheme 2; Table 2, entries
7–10). Alternatively, a number of N-substituted amino acids have
been recognized as pharmacologically potent compounds. For
this reason, the preformed N-carboxyl enaminones 2c–2e were
subjected to the reaction with indoline-2,3-dione 1, providing the
corresponding polycyclic substituted amino acid derivatives 3k–
3p in good to excellent yields. In addition, N-cyclopropyl enami-
none also gave the N-cyclopropyl fused acridine 3q in 74%
yield. To further expand the scope of N-substituted enaminone
substrates, different indoline-2,3-diones were used as model sub-
strates and various N-aryl enaminones including 4-chlorophenyl
2g, 4-bromophenyl 2h, 4-tolyl 2i, phenyl 2j, 3-chlorophenyl 2k,
and 4-methoxyphenyl 2l were examined. In all these cases, the
reactions proceeded smoothly to give the corresponding poly-
functionalized fused acridine substituted at multiple sites in good
yields with very high regioselectivities (Table 2, entries 18–32).
The results exhibit the scope and generality of the intermolecular
domino reaction with respect to a range of enaminone and isatin
substrates. Additionally, functional groups like bromide and
chloride were well tolerated. These functional groups provide
ample opportunity for further functional group manipulations,
for example by modern cross-coupling reactions.
In view of these results, we then investigated several differ-
ently substituted enaminones. When N-substituted 3-amino-
cyclohex-2-enones employed in the above system were replaced
by N-substituted 4-aminofuran-2(5H)-ones, the similar quinoline
derivatives were not generated. Instead, the reaction occurred in
another direction to form symmetrical multifunctionalized
indoles 4 that belong to another family of important scaffolds for
organic synthesis and drug design in pharmaceutical science
(Scheme 3).4 Two molecules of N-substituted 4-aminofuran-2
(5H)-ones were introduced into the final polysubstituted indoles.
Next, the reactions of N-substituted 4-aminofuran-2(5H)-ones
2m–2o with 1 in a 2 : 1.1 ratio were carried out under the above
conditions for a short period (15–20 min), providing structurally
diverse bis-furan-3-yl-substituted multifunctionalized indoles
4a–4d in 80–89% chemical yields.
We have planned to link two biologically important nuclei,
fused acridines and indoles, to generate a new set of compounds:
two-carbon-tethered fused acridine/indole pairs, using domino
heterocyclization of structurally diverse indoline-2,3-dione and
C2-tethered indol-3-yl enaminones, based on the fact that two
carbonyl groups of indoline-2,3-diones would undergo double
nucleophilic addition with enaminones, leading to ring-opening
of the indoline-2,3-diones through ring cleavage; and the new
formation of the amino group can further attack the carbonyl
group of the enaminones to form a pyrrole ring (Scheme 3).18
Based on the above analysis, we started this study by subjecting
a preformed 2-(indol-3-yl)ethyl substituted enaminone 2a to the
reaction with 5-chloroindoline-2,3-dione 1a in HOAc at 90 °C
under microwave irradiation. The reaction smoothly gave the
desired product 3a in 78% chemical yield. This good result
prompts us to further optimize the reaction conditions. The same
reactions were performed in different solvents, such as DMF,
EtOH, and toluene. All the cases scarcely proceeded in these sol-
vents. We reasoned that the acidic solvent can be used as a
Brønsted acid promotor and improve the yields of the desired
product 3. Next, this chemistry was carried out in EtCOOH,
HCOOH and CF3COOH. An incomplete reaction was observed
using EtCOOH or CF3COOH as an acidic solvent, while the
HCOOH gave a 64% yield of 3a. Therefore, HOAc was proven
to be the best base (Table 1, entry 5). Subsequently, the reaction
was performed in HOAc and repeated many times in different
temperatures in a sealed vessel under microwave irradiation for
20 min. The best yield of product 3a (84%) was obtained as the
reaction temperature was increased to 110 °C.
With these optimized conditions in hand, we examined the
scope of this new domino process by using various easily avail-
able starting materials. As revealed in Table 2, a range of invalu-
able fused acridine derivatives with different substituted patterns
can be synthesized in good to excellent yields. The reaction is
easy to perform simply by subjecting a mixture of indoline-2,3-
dione and various enaminones 2 in acetic acid to microwave
heating. Firstly, in the one-pot domino reaction for the synthesis
of two-carbon-tethered fused acridine/indole 3, the indoline-2,3-
dione scope of this interesting transformation was investigated.
Using various indoline-2,3-diones 1b–1f, such as 5-bromo (1b),
6-bromo (1c), 5-fluoro (1d), indoline-2,3-dione (1e), and 5-
methyl (1f), together with enaminone 2a, resulted in smooth
cyclization to the corresponding substituted fused acridine 3b–
3f. The pyridin-2-ylmethyl substituted enaminones 2b were con-
verted into the corresponding C-tethered fused acridine–pyridine
In all cases, the complexity of the resulting products from this
new reaction illustrates the remarkable regioselectivity of the
sequence, starting from very common and easily accessible start-
ing materials. Furthermore, the reaction occurred at a fast speed;
in fact, all cases can be finished within 16–32 min. Water is
nearly a sole by-product, which makes work-up convenient. In
most cases, the products can precipitate out after cold water was
poured into the reaction mixture. The structural elucidation was
8534 | Org. Biomol. Chem., 2012, 10, 8533–8538
This journal is © The Royal Society of Chemistry 2012

View Article Online
Table 2 Domino synthesis of fused acridine 3a–3ff and indoles 4a–4d under MW
Entry
Product
R1
Enaminones 2 (R)
Time/min
Yielda/%
1
2
3
4
5
6
7
8
9
10
3a
3b
3c
3d
3e
3f
3g
3h
3i
5-Chloro (1a)
5-Bromo (1b)
6-Bromo (1c)
5-Fluoro (1d)
H (1e)
5-Methyl (1f)
5-Chloro (1a)
5-Bromo (1b)
6-Bromo (1c)
H (1e)
2-(Indol-3-yl)ethyl (2a)
2-(Indol-3-yl)ethyl (2a)
2-(Indol-3-yl)ethyl (2a)
2-(Indol-3-yl)ethyl (2a)
2-(Indol-3-yl)ethyl (2a)
2-(Indol-3-yl)ethyl (2a)
Pyridin-2-ylmethyl (2b)
Pyridin-2-ylmethyl (2b)
Pyridin-2-ylmethyl (2b)
Pyridin-2-ylmethyl (2b)
20
24
24
25
26
30
30
30
28
30
84
82
78
80
76
75
82
75
70
72
3j
11
12
3k
3l
5-Chloro (1a)
5-Methyl 1f)
Carboxymethyl (2c)
Carboxymethyl (2c)
26
24
89
85
13
14
3m
3n
5-Chloro (1a)
H (1e)
2-Carboxyethyl (2d)
2-Carboxyethyl (2d)
28
28
74
71
15
16
3o
3p
H (1e)
5 Methyl 1f)
1-Carboxypropyl (2e)
1-Carboxypropyl (2e)
32
30
69
65
17
3q
5-Chloro (1a)
Cyclopropyl (2f)
32
74
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
3r
3s
3t
3u
3v
3w
3x
3y
5-Chloro (1a)
5-Chloro (1a)
5-Chloro (1a)
5-Bromo (1b)
5-Bromo (1b)
H (1e)
H (1e)
H (1e)
H (1e)
H (1e)
5-Methyl (1f)
5-Methyl (1f)
5-Methyl (1f)
5-Methyl (1f)
5-Methyl (1f)
5-Bromo (1b)
5-Methyl (1f)
H (1e)
4-Chlorophenyl (2g)
4-Bromophenyl (2h)
4-Tolyl (2i)
4-Tolyl (2i)
Phenyl (2j)
4-Chlorophenyl (2g)
4-Bromophenyl (2h)
4-Tolyl (2i)
18
16
18
20
22
25
26
26
28
30
32
30
30
28
28
18
15
20
18
84
88
89
82
85
78
81
83
75
71
79
84
80
73
82
80
85
89
84
3z
Phenyl (2j)
3aa
3bb
3cc
3dd
3ee
3ff
4a
4b
4c
4d
3-Chlorophenyl (2k)
4-Chlorophenyl (2g)
4-Tolyl (2i)
Phenyl (2j)
3-Chlorophenyl (2k)
4-Methoxyphenyl (2l)
4-Tolyl (2m)
4-Chlorophenyl (2n)
4-Bromophenyl (2o)
4-Tolyl (2m)
H (1e)
a Isolated yield.
Scheme 2 The synthesis of pyrrolo[2,3,4-kl]acridine 3.
Scheme 3 The synthesis of multifunctionalized indoles 4.
Org. Biomol. Chem., 2012, 10, 8533–8538 | 8535
This journal is © The Royal Society of Chemistry 2012

View Article Online
Scheme 4 The possible mechanism of formation of products 3.
facile and efficient strategy for the construction of a structurally
diverse fused acridine skeleton. The ready accessibility of the
starting materials, the broad compatibility of N-substituted enam-
inone substrates, and the generality of this process make the reac-
tion highly valuable in view of the synthetic and medicinal
importance of a multi-heterocyclic framework of this type. Fea-
tures of this strategy include short reaction times, convenient
one-pot operation, and high regioselectivity. Further investi-
gations are in progress in our laboratory to evaluate the process
with a broader range of substrates, and to synthesize more
complex products and test their biological activity.
Fig. 1 X-ray structure of 3t.
Experimental section
General
Microwave irradiation was carried out with Initiator 2.5 Micro-
wave Synthesizers from Biotage, Uppsala, Sweden. The reaction
temperatures were measured by an infrared detector during
microwave heating.
Fig. 2 X-ray structure of 3cc.
unequivocally determined by NMR spectroscopic analysis and
X-ray diffraction of single crystals that were obtained by slow
evaporation of the solvent, as in the cases of products 3t and 3cc
(Fig. 1 and 2). During these domino processes, the new for-
mation of pyrrole and pyridine rings was readily achieved in a
one-pot operation. Up to three sigma-bonds including two C–N
bonds were formed, accompanied by the cleavage of CvO and
C–N bonds of the indoline-2,3-diones 1 (Scheme 3).
On the basis of all the above results, the mechanism hypoth-
esis for the domino reaction has been proposed and is shown in
Scheme 4. The reaction involves the ring closure cascade reac-
tions, which consist of initial nucleophilic addition (2 to A),
intramolecular cyclization (A to B) and ring-opening of
indoline-2,3-dione 1 (B to C), re-cyclization and dehydration
(C to 3).
General procedure for the synthesis of compounds 3
Microwave heating: in a 10 mL reaction vial, indoline-2,3-dione
(1.1 mmol), enaminones (1 mmol) and AcOH (1.5 mL) were
mixed and stirred at room temperature for 3 min. Then the
system was heated for a given time at 110 °C under microwave
irradiation. Automatic stirring helped the mixing and uniform
heating of the reactants. Upon completion, monitored by TLC,
the reaction mixture was cooled to room temperature and then
poured into the cold water. The solid product was collected by
Büchner filtration and washed with water and EtOH (95%), and
subsequently dried and recrystallized from EtOH (95%) to give
the pure product.
General procedure for the synthesis of compounds 4
Microwave heating: in a 10 mL reaction vial, indoline-2,3-dione
(1.1 mmol), N-substituted 4-aminofuran-2(5H)-ones (2 mmol)
and AcOH (1.5 mL) were mixed and stirred at room temperature
for 3 min. Then the system was heated for a given time at
110 °C under microwave irradiation. Upon completion, moni-
tored by TLC, the reaction mixture was cooled to room tempera-
ture and then poured into the cold water. The solid product was
Conclusions
In summary, we have described Brønsted acid-promoted domino
heterocyclization as an alternative method for the synthesis of a
set of C2-tethered fused acridine/indole pairs and C-tethered
fused acridine/pyridine pairs with concomitant formation of
three sigma-bonds in a one-pot reaction. This reaction provides a
8536 | Org. Biomol. Chem., 2012, 10, 8533–8538
This journal is © The Royal Society of Chemistry 2012

View Article Online
collected by Büchner filtration and washed with water and EtOH
(95%), and subsequently dried and recrystallized from EtOH
(95%) to give the pure product 4.
ArH), 6.71 (d, J = 8.0 Hz, 1H, ArH), 4.67 (s, 4H, CH2), 2.28
(s, 6H, CH3).
13C NMR (100 MHz, DMSO-d6) (δ, ppm): 177.8, 171.5,
163.3, 141.6, 136.1, 134.8, 134.1, 130.1, 129.6, 127.8, 123.8,
112.6, 110.7, 65.5, 48.9, 20.4.
2-(2-(1H-Indol-3-yl)ethyl)-4,4-dimethyl-4,5-dihydropyrrolo[2,3,
4-kl]acridin-1(2H)-one (3e). Yellow solid; mp: 230.1–230.9 °C.
IR (KBr, ν, cm−1): 3693, 3172, 1688, 1651, 1584, 1338,
1031, 733.
HRMS (ESI) m/z: calcd for C30H25BrN3O5: 586.09778
[M + H]+; found: 586.09789.
1H NMR (400 MHz, DMSO-d6) (δ ppm): 10.80 (s, 1H, NH),
8.53 (d, J = 8.0 Hz, 1H, ArH), 8.09 (d, J = 8.4 Hz, 1H, ArH),
7.78 (t, J = 7.6 Hz, 1H, ArH), 7.70 (t, J = 7.6 Hz, 1H, ArH),
7.53 (d, J = 7.6 Hz, 1H, ArH), 7.32 (d, J = 8.0 Hz, 1H, ArH),
7.13 (s, 1H, ArH), 7.04 (t, J = 7.6 Hz, 1H, ArH), 6.91 (t, J =
7.6 Hz, 1H, CH), 5.45 (s, 1H, CH), 4.04 (t, J = 6.4 Hz, 2H,
CH2), 3.09 (t, J = 6.4 Hz, 2H, CH2), 2.98 (s, 2H, CH2), 1.08 (s,
6H, CH3).
Acknowledgements
We are grateful for financial support from the National Science
Foundation of China (nos. 21232004, 21272095, 21072163, and
21102124), the Priority Academic Program Development
(PAPD) of Jiangsu Higher Education Institutions, Science Foun-
dation in Interdisciplinary Major Research Project of Xuzhou
Normal University (no. 09XKXK01), the NSF of Jiangsu Edu-
cation Committee (11KJB150016), and Jiangsu Science and
Technology Support Program (no. BE2011045), and Doctoral
Research Foundation of Xuzhou Normal Univ. (XZNU, no.
10XLR20).
13C NMR (100 MHz, DMSO-d6) (δ ppm): 166.4, 154.5,
148.8, 136.2, 132.1, 129.3, 129.2, 127.6, 127.3, 126.0, 124.3,
123.2, 123.2, 121.8, 120.9, 118.2, 118.1, 118.0, 112.7, 111.4,
110.9, 43.2, 40.7, 36.4, 30.1, 24.3.
HRMS (ESI) m/z: calcd for C26H24N3O: 394.1919; found:
394.1942.
Notes and references
2-(4,4-Dimethyl-1-oxo-4,5-dihydropyrrolo[2,3,4-kl]acridin-2(1H)-
yl)butanoic acid (3o). Yellow solid; mp: 222.3–222.4 °C.
IR (KBr, ν, cm−1): 3694, 2961, 1694, 1655, 1524, 1463,
1414, 1339, 1299, 1254, 1223, 1152, 1045, 913, 871.
1H NMR (400 MHz, CDCl3) (δ ppm): 8.66 (d, J = 8.0 Hz,
1H, ArH), 8.18 (d, J = 8.4 Hz, 1H, ArH), 7.72 (t, J = 7.6 Hz,
1H, ArH), 7.64 (t, J = 7.4 Hz, 1H, ArH), 5.63 (s, 1H, CH),
5.32–4.93 (m, 1H, CH), 3.20 (s, 2H, CH2), 2.46–2.27 (m, 1H,
CH), 2.26–2.11 (m, 1H, CH), 1.32 (s, 3H, CH3), 1.26 (s, 3H,
CH3), 0.96 (t, J = 7.2 Hz, 3H, CH3).
1 (a) P. W. Groundwaater and M. Ali Munawar, Adv. Heterocycl. Chem.,
1998, 70, 88; (b) A. Kuzuya, R. Mizoguchi, T. Sasayama, J.-M. Zhou
and M. Komiyama, J. Am. Chem. Soc., 2004, 126, 1430;
(c) M.-K. Cheng, C. Modi, J. C. Cookson, I. Hutchinson, R. A. Heald,
A. J. McCarroll, S. Missailidis, F. Tanious, W. D. Wilson, J.-L. Mergny,
C. A. Laughton and M. F. G. Stevens, J. Med. Chem., 2008, 51, 963;
(d) J. C. Cookson, R. A. Heald and M. F. G. Stevens, J. Med. Chem.,
2005, 48, 7198; (e) I. Antonini, P. Polucci, A. Magnano, S. Sparapani
and S. Martelli, J. Med. Chem., 2004, 47, 5244; (f) K. K. Gruner and
H.-J. Knolker, in Heterocycles in Natural Product Synthesis, ed.
K. C. Majumdar and S. Chattopadhyay, Wiley-VCH, Weinheim,
Germany, 2011, pp. 341–376.
2 (a) W. D. Inman, M. O’Neill-Johnson and P. Crews, J. Am. Chem. Soc.,
1990, 112, 1; (b) E. Gimenez-Arnau, S. Missailidis and M. F. G. Stevens,
Anti-Cancer Drug Des., 1998, 13, 431.
3 P. J. McCarthy, T. P. Pitts, G. P. Gunawardana, M. Kelly-Borges and
S. A. Pomponi, J. Nat. Prod., 1992, 55, 1664.
4 (a) D. A. Horton, G. T. Bourne and M. L. Smythe, Chem. Rev., 2003,
103, 893; (b) W. J. Houlihan, W. A. Remers and R. K. Brown, Indoles,
Wiley, New York, NY, 1992, Part I; (c) R. J. Sundberg, The Chemistry of
Indoles, Academic Press, New York, 1996.
5 (a) A. Casapullo, G. Bifulco, I. Bruno and R. J. Riccio, J. Nat. Prod.,
2000, 63, 447; (b) B. Bao, Q. Sun, X. Yao, J. Hong, C. O. Lee, C.
J. Sim, K. S. Im and J. H. J. Jung, J. Nat. Prod., 2005, 68, 711;
(c) T. Kouko, K. Matsumura and T. Kawasaki, Tetrahedron, 2005, 61,
2309; (d) K. Kaniwa, M. A. Arai, X. Li and M. Ishibashi, Bioorg. Med.
Chem. Lett., 2007, 17, 4254.
13C NMR (100 MHz, CDCl3) (δ ppm): 173.1, 167.5, 154.4,
131.5, 129.8, 128.5, 128.0, 126.8, 125.2, 124.2, 122.5, 119.2,
55.4, 43.2, 37.2, 30.9, 30.8, 22.9, 10.8.
HRMS (ESI) m/z: calcd for C20H21N2O3: 337.1552 [M + H]+;
found: 337.1522.
2-(4-Bromophenyl)-9-chloro-4,4-dimethyl-4,5-dihydropyrrolo-
[2,3,4-kl]acridin-1(2H)-one (3s). Yellow solid, mp: 177–178 °C.
IR (KBr, ν, cm−1): 2957, 1703, 1646, 1602, 1508, 1492,
1441, 1365, 1341, 1209, 1152, 1139, 1086, 1077, 889.
1H NMR (400 MHz, DMSO-d6) (δ, ppm): 8.46 (s, 1H, ArH),
8.15 (d, J = 8.8 Hz, 1H, ArH), 7.85–7.78 (m, 3H, ArH), 7.51 (d,
J = 8.0 Hz, 2H, ArH), 5.87 (s, 1H, CH), 3.17 (s, 2H, CH2), 1.28
(s, 6H, CH3).
6 S. Zhu, S. Ji, X. Su, C. Sun and Y. Liu, Tetrahedron Lett., 2008, 49,
1777.
7 A. M. Farghaly, N. S. Habib, M. A. Khalil, O. A. E. Sayed and
J. Alexandria, Pharm. Sci., 1989, 3, 9.
13C NMR (100 MHz, DMSO-d6) (δ, ppm): 167.6, 165.3,
155.5, 147.4, 133.6, 132.3, 131.8, 131.4, 130.9, 129.9, 128.4,
122.4, 121.9, 120.4, 120.3, 117.1, 43.2, 37.0, 30.7, 30.2.
HRMS (ESI) m/z: calcd for C22H17BrClN2O, 439.0213
[M + H]+; found: 439.0190.
8 (a) K. Alex, A. Tillack, N. Schwarz and M. Beller, Angew. Chem., Int.
Ed., 2008, 47, 2304; (b) P. Kohling, A. M. Schmidt and P. Eilbracht, Org.
Lett., 2003, 5, 3213; (c) J. L. Rutherford, M. P. Rainka and
S. L. Buchwald, J. Am. Chem. Soc., 2002, 124, 15168;
(d) C. M. Coleman and D. F. O’Shea, J. Am. Chem. Soc., 2003, 125,
4054; (e) J. R. Dunetz and R. L. Danheiser, J. Am. Chem. Soc., 2005,
127, 5776; (f) S.-L. Cui, J. Wang and Y.-G. Wang, J. Am. Chem. Soc.,
2008, 130, 13526; (g) J. Barluenga, M. Trincado, E. Rubio and
J. M. Gonzalez, Angew. Chem., Int. Ed., 2003, 42, 2406; (h) B. M. Trost
and A. McClory, Angew. Chem., Int. Ed., 2007, 46, 2074; (i) S. Agarwal,
S. Caemmerer, S. Filali, W. Froehner, J. Knoell, M. P. Krahl, K. R. Reddy
and H.-J. Knoelker, Curr. Org. Chem., 2005, 9, 1601.
3,3′-(5-Bromo-2-oxoindoline-3,3-diyl)bis(4-(p-tolylamino)furan-
2(5H)-one) (4a). White solid; mp: 267.7–279.4 °C.
IR (KBr, ν, cm−1): 3337, 3036, 2861, 1750, 1716, 1604,
1475, 1056, 818, 759.
1H NMR (400 MHz, DMSO-d6) (δ, ppm): 10.52 (s, 1H, NH),
8.97 (s, 2H, NH), 7.42 (d, J = 2.0 Hz, 1H, ArH), 7.33 (s, 1H,
ArH), 7.14 (d, J = 8.0 Hz, 4H, ArH), 7.00 (d, J = 8.0 Hz, 4H,
9 (a) J. Barluenga, F. Rodriguez and F. J. Fananas, Chem.–Asian J., 2009,
4, 1036; (b) R. Bernini, G. Fabrizi, A. Sferrazza and S. Cacchi, Angew.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8533–8538 | 8537

View Article Online
Chem., Int. Ed., 2009, 48, 8078; (c) Z. Shi, C. Zhang, S. Li, D. Pan,
S. Ding, Y. Cui and N. Jiao, Angew. Chem., Int. Ed., 2009, 48, 4572;
(d) P. Thansandote and M. Lautens, Chem.–Eur. J., 2009, 15, 5874;
(e) S. Wuertz, S. Rakshit, J. J. Neumann, T. Droege and F. Glorius,
Angew. Chem., Int. Ed., 2008, 47, 7230; (f) W. Yu, Y. Du and K. Zhao,
Org. Lett., 2009, 11, 2417; (g) M. Zhang, Adv. Synth. Catal., 2009, 351,
2243.
J. Org. Chem., 2004, 69, 3735; (h) A. V. K. Prasad and Y. Shimizu,
J. Am. Chem. Soc., 1989, 111, 6476.
14 (a) B. Jiang, M.-S. Yi, F. Shi, S.-J. Tu, S. Pindi, P. McDowell and G. Li,
Chem. Commun., 2012, 808; (b) B. Jiang, Q.-Y. Li, H. Zhang, S.-J. Tu,
S. Pindi and G. Li, Org. Lett., 2012, 14, 700; (c) B. Jiang, C. Li, F. Shi,
S.-J. Tu, P. Kaur, W. Wever and G. Li, J. Org. Chem., 2010, 75, 2962;
(d) B. Jiang, S.-J. Tu, P. Kaur, W. Wever and G. Li, J. Am. Chem. Soc.,
2009, 131, 11660; (e) C. Cheng, B. Jiang, S.-J. Tu and G. Li, Green
Chem., 2011, 13, 2107.
15 (a) B. Jiang, G. Zhang, N. Ma, F. Shi, S.-J. Tu, P. Kaur and G. Li, Org.
Biomol. Chem., 2011, 9, 3834; (b) B. Jiang, X. Wang, F. Shi, S.-J. Tu and
G. Li, Org. Biomol. Chem., 2011, 9, 4025; (c) B. Jiang, W. J. Hao,
J. P. Zhang, S.-J. Tu and F. Shi, Org. Biomol. Chem., 2009, 7, 1171;
(d) B. Jiang, F. Shi and S.-J. Tu, Curr. Org. Chem., 2010, 14, 357;
(e) J.-Y. Liu, H. Zhang, B.-M. Feng, B. Jiang, S.-L. Wang and S.-J. Tu,
Org. Biomol. Chem., 2012, 10, 5036; (f) J. Li, Y. Yu, M.-S. Tu, B. Jiang,
S.-L. Wang and S.-J. Tu, Org. Biomol. Chem., 2012, 10, 5361;
(g) S.-L. Wang, F. Y. Wu, C. Cheng, G. Zhang, Y.-P. Liu, B. Jiang, F. Shi
and S.-J. Tu, ACS Comb. Sci., 2011, 13, 135.
16 (a) K. V. V. Ananthalakshmi, I. O. Edafiogho and S. B. Kombian, Epi-
lepsy Res., 2007, 76, 85; (b) A. El-Hashim, S. Yousefi, I. Edafiogho,
R. Raghupathy, M. Yousif and H.-U. Simon, Eur. J. Pharmacol., 2010,
632, 73; (c) M. Abass and B. B. Mostafa, Bioorg. Med. Chem., 2005, 13,
6133; (d) K. Scott, G. Rankin, J. Stables, M. Alexander, I. Edafiogho,
V. Farrar, K. Kolen, J. Moore, L. Sims and A. Tonnut, J. Med. Chem.,
1995, 38, 4033; (e) H. Lida, Y. Yuasa and C. Kibayashi, J. Org. Chem.,
1979, 44, 4033.
17 (a) B. Stanovnik and J. Svete, Chem. Rev., 2004, 104, 2433;
(b) J. D. White and D. C. Ihle, Org. Lett., 2006, 8, 1081; (c) S.-J. Tu,
B. Jiang, R.-H. Jia, J.-Y. Zhang, Y. Zhang, C. S. Yao and F. Shi, Org.
Biomol. Chem., 2006, 4, 3664; (d) J. Huang, Y. Liang, W. Pan and
D. Dong, Org. Lett., 2007, 9, 5345; (e) I. Yavari, Z. Hossaini and
M. Sabbaghan, Tetrahedron Lett., 2008, 49, 844; (f) G.-W. Wang and
C.-B. Miao, Green Chem., 2006, 8, 1080; (g) X. J. Wu, X. P. Xu,
X. M. Su, G. Chen, Y. Zhang and S. J. Ji, Eur. J. Org. Chem., 2009,
4963; (h) X. J. Wu, R. Jiang, B. Wu, X. M. Su, X. P. Xu and S. J. Ji, Adv.
Synth. Catal., 2009, 351, 3150.
10 (a) J. A. Feducia and M. R. Gagne, J. Am. Chem. Soc., 2008, 130, 592;
(b) R. A. Yoder and J. N. Johnston, Chem. Rev., 2005, 105, 4730;
(c) J. K. Sutherland, in Comprehensive Organic Synthesis, ed.
B. M. Trost, Pergamon Press, Elmsford, NY, 1991, vol. 1, pp. 341–377;
(d) K. U. Wendt, G. E. Schultz, E. J. Corey and D. R. Liu, Angew. Chem.,
Int. Ed., 2000, 39, 2812.
11 (a) K. C. Nicolaou and J. S. Chen, Chem. Soc. Rev., 2009, 38, 2993;
(b) K. C. Nicolaou, D. J. Edmonds and P. G. Bulger, Angew. Chem., Int.
Ed., 2006, 45, 7134; (c) K. C. Nicolaou, P. S. Baran, Y.-L. Zhong and
K. Sugita, J. Am. Chem. Soc., 2002, 124, 2212; (d) J. J. Topczewski,
M. P. Callahan, J. D. Neighbors and D. F. Wiemer, J. Am. Chem. Soc.,
2009, 131, 14630; (e) J.-C. Wasilke, S. J. Obrey, T. Baker and
G. C. Bazan, Chem. Rev., 2005, 105, 1001.
12 (a) L. F. Tietze, Chem. Rev., 1996, 96, 115; (b) L. F. Tietze, G. Brasche
and K. Gerike, Domino Reactions in Organic Chemistry, Wiley-VCH,
Weinheim, 2006; (c) A. Padwa and S. K. Bur, Tetrahedron, 2007, 63,
5341; (d) A. Padwa, Chem. Soc. Rev., 2009, 38, 3072; (e) L. F. Tietze,
T. Kinzel and C. C. Brazel, Acc. Chem. Res., 2009, 42, 367;
(f) B. Groenendaal, E. Ruijter and R. V. A. Orru, Chem. Commun., 2008,
5474; (g) N. Ismabery and R. Lavila, Chem.–Eur. J., 2008, 14, 8444;
(h) J. D. Sunderhaus and S. F. Martin, Chem.–Eur. J., 2009, 15, 1300;
(i) B. Ganem, Acc. Chem. Res., 2009, 42, 463.
13 (a) C. I. Turner, R. M. Williamson, P. Tumer and M. S. Sherburn, Chem.
Commun., 2003, 1610; (b) J. S. Clark, J. Myatt, C. Wilson, L. Roberts
and N. Walshe, Chem. Commun., 2003, 1546; (c) J. Justicia, J. E. Oltra
and J. M. Cuerva, J. Org. Chem., 2004, 69, 5803; (d) A.-L. Dhimane,
C. Aïssa and M. Malacria, Angew. Chem., Int. Ed., 2002, 41, 3284;
(e) L. Boiteau, J. Boivin, A. Liard, B. Quiclet-Sire and S. Z. Zard,
Angew. Chem., Int. Ed., 1998, 37, 1128; (f) H. Li, J. L. Petersen and
K. K. Wang, J. Org. Chem., 2003, 68, 5512; (g) A. Padwa,
M. B. Brodney, S. M. Lynch, P. Rashatasakhon, Q. Wang and H. Zhang,
18 (a) F. Yu, S. Yan, L. Hu, Y. Wang and J. Lin, Org. Lett., 2011, 13, 4782.
8538 | Org. Biomol. Chem., 2012, 10, 8533–8538
This journal is © The Royal Society of Chemistry 2012