A one-pot synthetic approach to the functionalized isomeric ellipticine derivatives through an imino Diels-Alder reaction

Article abstract of DOI:10.1016/j.tetlet.2009.01.020

An efficient, three component, one-pot synthesis of new isomeric ellipticine derivatives prepared through an imino Diels-Alder reaction of 3-aminocarbazoles and substituted benzaldehydes with electron-rich alkenes such as 3,4-dihydro-2H-pyran, 2,3- dihydr

Full text of DOI:10.1016/j.tetlet.2009.01.020

Tetrahedron Letters 50 (2009) 1243–1248
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A one-pot synthetic approach to the functionalized isomeric ellipticine
derivatives through an imino Diels–Alder reaction
*
Vikram Gaddam, Rajagopal Nagarajan
School of Chemistry, University of Hyderabad, Central University (PO), Hyderabad 500046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, three component, one-pot synthesis of new isomeric ellipticine derivatives prepared through
an imino Diels–Alder reaction of 3-aminocarbazoles and substituted benzaldehydes with electron-rich
alkenes such as 3,4-dihydro-2H-pyran, 2,3- dihydrofuran and ethyl vinyl ether catalyzed by InCl3
(10 mol %) in ionic liquid is reported. In the case of substituted benzaldehydes, reductive amination is
observed.
Received 24 October 2008
Revised 31 December 2008
Accepted 9 January 2009
Available online 13 January 2009
Ó 2009 Published by Elsevier Ltd.
Keywords:
Heterocycles
Isoellipticine
Cycloaddition
Ionic liquid
Indium trichloride
Nitrogen-containing heterocycles are widespread in nature and
possess a broad spectrum of interesting biological properties. Ellip-
ticine, an alkaloid isolated from Apocyanaceae plants, and several
of its derivatives exhibit promising results in the treatment of oste-
olytic breast cancer metastases, brain tumors, kidney sarcoma, and
myeloblastic leukemia.1 More recent studies have also indicated
activity against HIV.2 The main reason for the interest in ellipticine
and its derivatives for clinical purposes is their high efficiency
against several types of cancer, limited toxic side effects, and a
complete lack of hematological toxicity.3 Ellipticine is an antineo-
plastic agent, the mode of action of which was considered to be
based mainly on DNA intercalation and/or inhibition of topoiso-
merase II.1,3
Ellipticine has proven to be a popular target for synthesis, and a
wide variety of strategies have been reported.4–6 Similarly, the
structurally related aryl- and heteroaryl annulated carbazoles have
also received considerable synthetic attention.4–7 Despite the great
interest that has given rise to much synthetic work on ellipticine
and its derivatives, very little attention has been focused on the
synthesis of its isomers or on fusion with other biologically impor-
tant molecules.8
carbocyclic and heterocyclic compounds.9 Moreover, cycloaddi-
tion reactions may offer wide scope in the generation of molecu-
lar diversity through the variation of the structures of both
reactants, diene and dienophile. The reaction of imines with elec-
tron-rich dienophiles has been reported to be catalyzed by Lewis
acids.10 In this Letter, we present our recent results demonstrat-
ing that imines derived from substituted benzaldehydes and
3-aminocarbazoles are excellent substrates for an intermolecular
imino Diels–Alder reaction with electron-rich dienophiles cata-
lyzed by InCl3 (10 mol %) in [Emim]-[BF4] to provide highly
functionalized isomeric ellipticine derivatives with high diastere-
oselectivity. Ionic liquids are increasingly used as reaction media
in organic synthesis as they offer a wide range of advantages over
classical organic solvents. [Emim]-[BF4] has been exploited as
an efficient Brønsted acid promoter in various organic transfor-
mations.11
Construction of the polycyclic isomeric ellipticine ring systems
employing the cycloaddition of imine derived from 9-ethyl-3-
aminocarbazole and benzaldehyde in [Emim]-[BF4] at 100 °C
underwent an intermolecular [4+2] cycloaddition reaction with
3,4-dihydro-2H-pyran in the presence of Lewis acid to yield 9-
ethyl-5-phenyl-2,3,4,4a,5,6,9,13d-octahydropyrano[20,30:4,5]pyr-
ido[2,3-c] carbazole 4b and 4ab as a mixture of diastereomers,
where the cis isomer 4b is the major product along with regioisom-
er 4abc (Scheme 1).
The imino Diels–Alder [4+2] cycloaddition reaction has been
established as a powerful synthetic tool for the construction of
a polycyclic ring system in a stereo- and regio-controlled manner
and has been widely used in the preparation of a wide range of
The reactions proceed smoothly in the presence of Lewis
acids or Brønsted acids, but diastereoselectivity depends on the
nature of the catalyst (Table 1). And in all cases cis diastereomer
* Corresponding author. Tel.: +91 40 23134831; fax: +91 40 23012460.
E-mail address: rnsc@uohyd.ernet.in (R. Nagarajan).
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.01.020

1244
V. Gaddam, R. Nagarajan / Tetrahedron Letters 50 (2009) 1243–1248
(4a)
H
(4a)
H
(5)
H
(5)
H
NH
O
(5)
H
NH
CHO
O
NH2
+
(4a)
H
HN
H
H
Lewis acid
+
+
CH3CN/ 100 oC
+
H
O
N
O
N
(13b)
N
N
Et
1b
Et
Et
4ab
Et
4abc
2a
3b
4b
Scheme 1. Synthesis of isomeric ellipticine derivatives.
Table 1
Optimization of reaction conditions
Entry
Catalyst
Time (h)
Yield (%)
Product ratioa (4b/4abc/4c)
1
2
3
4
5
6
7
8
9
BF3ꢁOEt2 (20 mol %)
CF3COOH (20 mol %)
CAN (20 mol %)
[Emim]-[BF4]
[Emim]-[BF4]/InCl3/rt
[Emim]-[PF6]/InCl3/rt
[Emim]-[BF4]/InCl3/50 °C
[Emim]-[BF4]/InCl3/70 °C
[Emim]-[BF4]/InCl3/100 °C
[Emim]-[BF4]/La(OTf)3/100 °C
24
24
12
24
24
24
12
05
01
02
65
70
86
41
76
72
81
85
90
80
62:23:15
67:17:16
83:11:06
61:29:10
77:20:03
74:22:04
70:25:05
77:19:04
78:22:0
10
76:24:0
a
Yields refer to purified product after column chromatography.
4b is the major product. Surprisingly, we have also observed a
minor product 4abc, which occurs through cyclization with the
second position of aminocarbazole. Lower yields and longer reac-
tion time are observed in [Emim]-[BF4], without the catalyst.
Among the catalysts screened, InCl3 and La(OTf)3 were found
to be better in [Emim]-[BF4]. However, compared to InCl3,
La(OTf)3 gives a low yield (80%) and requires a longer reaction
time (2 h). The positive role of indium chloride in the imino
Diels–Alder reaction was reported earlier.12 After the addition
of InCl3 (10 mol %), the reaction rate is faster and better diaste-
reoselectivity is observed at 100 °C. Ionic liquids having the
counter-ion [PF6ꢀ] have a lower yield as compared with [BF4ꢀ].
Further increase in the temperature did not improve the regio-
isomer ratio. The stereochemistry was assigned on the basis of
the coupling constant values and also by NOE and 2D NOESY
studies. The tetrahydropyran and the six-membered piperidine
rings were cis fused, as indicated by the coupling constant
J13d–4a = 5.7 Hz between H13d (d 5.87) and H4a (d 2.45). Also,
J4a–5 = 2.3 Hz, where H5 (d 4.64) in 4b and the presence of NOEs
between H13d–H4a and H4a–H5 confirm that these three protons
are cis to each other.
In 4ab, J13d-4a = 3.5 Hz between H13d (d 5.21) and H4a (d 2.28)
show cis coupling but J4a-5 = 15.2 Hz where H5 (d 4.82) are trans
and NOE also confirms that H13d–H4a are cis to each other and
H4a–H5 are in trans. In the case of 4abc, H13b (d 5.56), H4a (d
2.29), and H5 (d 4.73) are cis with the coupling constants J13d-
4a = 4.9 Hz and J4a-5 = 2.4 Hz and NOE also confirms the same
thing. 2D NOESY also supports this stereochemistry. Isomers 4b,
4ab, and 4abc were also confirmed by single-crystal X-ray diffrac-
tion analysis. The crystal structures of 4b and 4abc are shown in
Figure 1.13
Extending this methodology further, we have carried out the
imino Diels–Alder reaction with various substituted amines in
the presence of InCl3 (10 mol %) under optimized conditions.
The results are summarized in Table 2. In most cases, the corre-
sponding imino Diels–Alder products 4a–c were obtained in
Figure 1. ORTEP diagrams of 4b and 4abc.

V. Gaddam, R. Nagarajan / Tetrahedron Letters 50 (2009) 1243–1248
1245
Table 2
The intermolecular imino Diels–Alder reaction of various substituted amines
H
R2
H
CHO
NH2
+
H
H3C
HN
O
H
NH
H
InCl3 (10 mol %)
+
[Emim]-[BF4]/ 100 oC
+
N
O
1-2 h
H
CH3
O
R3
N
R1
N
2a
3b
R1
Ph
R1 = R2 = R3 = H, 1a
R1 = C2H5, R2 = R3 = H, 1b
4c
4a-b
R1 = C6H7, R2 = R3 = CH3, 1c
Entry
Reactant
Product
Yield (%)
Product ratio
H
O
H
H
NH
1
1a
89
95:05
N
H
4a
2
3
1b
1c
4a and 4abc
90
71
78:22
93:07
H
H
H C
3
N
H
H
N
O
CH
3
Ph
4c
good yields (Table 2). But in the case of 1c, having substituents
on the first and fourth positions (R3 = R4 = CH3), the correspond-
ing product (4c) was obtained in only 71% yield, and this may be
due to the steric hindrance caused by the methyl groups. The X-
ray crystal structure of (4c) is presented in Figure 2.13
2,3-Dihydrofuran undergoes a cycloaddition reaction with elec-
tron deficient dienes generated from 9-ethyl-3-aminocarbazole
and benzaldehyde to give 4d in 85% yield with 97:03 diastereose-
lectivity (Table 3). Similarly, ethyl vinyl ether reacts with the imine
derived from benzaldehyde and aminocarbazole in the presence of
InCl3 (10 mol %) in ionic liquid to provide cycloadduct 4e in a good
yield. The reactions are performed at room temperature, but at 100
°C lower yields and side products were observed. Ethyl vinyl ether
and dihydrofuran also exhibited behavior similar to dihydropyran
with respect to the stereochemistry of the products. The coupling
constants obtained from 1H NMR and 2D NOESY support this
stereochemistry.
To prove the generality of this reaction, we have also exam-
ined the reactions of substituted benzaldehydes under the same
reaction conditions. The results are summarized in Table 4. The
reaction proceeds smoothly to afford cycloadducts 4f–i, and a
surprisingly reductive amination is also observed as a side reac-
tion (products 4fa–ia). The same products were obtained when
acetonitrile was used as the solvent without the use of ionic
liquid and InCl3 is used as a catalyst (with La(OTf)3, a similar
reactivity is observed). We assume this reduction may be due
to the oxidation of 2,3-dihydro-2H-pyran, since without the
use of pyran no reductive amination occurred. The X-ray crystal
structure of 4ia is shown in Figure 3.13 By using a larger amount
of dihydropyran (10 equiv), the yield of cycloadduct 4f improved
from 60% to 88%. Instead of substituted benzaldehydes, we have
also checked with N-methylindole-2-carboxaldehyde, which
gives only the single product 4j under the same reaction
conditions.
In summary, we have described a novel and practical method
for the synthesis of new isomeric ellipticine derivatives through
an intermolecular imino Diels–Alder reaction with high diastere-
oselectivity. This procedure has the advantage of high yields, easy
availability, and flexibility of starting materials, short reaction
times, and good diastereoselectivity.14
Figure 2. ORTEP diagram of 4c.

1246
V. Gaddam, R. Nagarajan / Tetrahedron Letters 50 (2009) 1243–1248
Table 3
The intermolecular imino Diels–Alder reaction of various electron-rich dienophiles
n = 0,1
( )
H
H
EtO
CHO
NH 2
+
H
NH
O
H
H
NH
(
)n
InCl3 (10 mol %)
[Emim]-[BF4]/ 100 o
1-2 h
+
or
C
OEt
3c
or
O
N
n = 0, 3a
n = 1, 3b
N
Et
N
1b
2a
Et
Et
4e
4b, 4abc and 4d
Entry
Reactant
Product
Yield (%)
dr ratio
H
O
H
H
NH
1
2
3
3a
3b
3c
85
90
92
97:03
78:22
96:04
N
Et
4d
4a and 4abc
EtO
H
H
NH
N
Et
4e
Table 4
Synthesis of isomeric ellipticine derivatives with substituted aldehydes
R
R
H
CHO
NH2
+
H
O
NH
NH
H
InCl3 (10 mol %)
+
[Emim]-[BF4]/ 100 o
1-2 h
C
+
N
O
N
Et
R
2a-e
N
Et
3b
Et
4fa-ia
1b
4f-i
Entry
1
R
Products
H
4a and 4abc
Cl
O
H
Cl
H
2
Cl
NH
H
NH
N
Et
4f (60 %)
N
4fa (21 %)
Et
Br
Br
H
O
H
3
Br
H
NH
NH
N
4g (55 %)
N
Et
4ga (25 %)
Et

V. Gaddam, R. Nagarajan / Tetrahedron Letters 50 (2009) 1243–1248
1247
Table 4 (continued)
Entry
R
Products
CH
3
CH3
H
O
H
4
CH3
NH
H
NH
N
Et
4h (52 %)
N
4ha (40 %)
Et
OCH3
O
H
OCH3
H
5
OCH3
NH
H
NH
N
Et
4i (48 %)
N
4ia (40 %)
Et
O
H
H
CHO
6
N
N
H
NH
N
CH
H3C
3
Et
4j ( 67 %)
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Figure 3. ORTEP diagrams of 4ia.
Acknowledgments
We gratefully acknowledge DST for providing financial assis-
tance and single crystal X-ray diffractometer facility in our school.
G.V. thanks CSIR for a Senior Research Fellowship. We thank Dr. P.
Raghavaiah for his help in solving the crystal structures and Mr. S.
Satyanaryana for NMR experiments.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.01.020.
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References and notes
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H. -H.; Yang, F.; Cui, P.; Tang, J.; He, M.-Y. Tetrahedron Lett 2004, 45, 4963–
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parameters: a 8.694(3), b 10.223(4), c 14.049(5), a 91.585(5), b 107.682(5), c
ꢁ
107.141(5) and space group P1. The CCDC deposition number for 4c is
700696; molecular formula: C33H32N2O, chemical formula weight 472.61,
monoclinic, unit cell parameters: a 12.009(2), b 23.983(5), c 8.8101(17), b
91.916(4) and space group P21/c.
14. Typical procedure for the imino Diels–Alder reaction of 4b: To a solution of
benzaldehyde (0.106 g, 1.0 mmol), 9-ethyl-3-aminocarbazole (0.210 g, 1.0
mmol), 3,4-dihydro-2H-pyran, (0.210 g, 2.5 mmol) in 0.5 g of ionic liquid was
added InCl3 (0.022 g, 10 mol %), and the reaction stirred at 100 °C for an
appropriate time. After the completion of the reaction, as indicated by the TLC,
the crude reaction mass was poured into water (50 mL) and extracted with
DCM (3 ꢂ 20 mL). The organic layer was dried over Na2SO4 and distilled under
reduced pressure. The residue was chromatographed over basic alumina and
eluted with hexane–ethyl acetate to afford 0.268 g (70 %) of 4b. Mp 158–159
13. The CCDC deposition number for 4b is 700692; molecular formula:
C26H26N2O, chemical formula weight 382.49, monoclinic, unit cell
parameters:
a 12.171(4), b 19.615(6), c 8.481(3), b 99.583(5) and space
group P21/c. The CCDC deposition number for 4ab is 700691; molecular
formula: C52H54N4O2, chemical formula weight 766.99, monoclinic, unit cell
parameters: a 17.345(6), b 9.953(3), c 28.955(7), b 124.743(14) and space
group P21/c. The CCDC deposition number for 4abc is 700693; molecular
formula: C26H26N2O, chemical formula weight 382.49, monoclinic, unit cell
parameters: a 12.448(3), b 8.554(2), c 19.291(5), b 95.512(4) and space group
P21/n. The CCDC deposition number for 4ia is 700694; molecular formula:
C22H22N2O, chemical formula weight 330.42, monoclinic, unit cell
parameters: a 21.435(4), b 10.400(2), c 8.2300(16), b 92.72(3) and space
group P21/c. The CCDC deposition number for 4j is 700695; molecular
formula: C29H29N3O, chemical formula weight 435.55, triclinic, unit cell
°C; IR (KBr): 3369, 3026, 2941, 1585, 1153, 1086, 983, 929 cmꢀ1 1H NMR (400
;
MHz, TMS, CDCl3) d: 8.61 (1H, d, J = 8.1 Hz); 7.51 (2H, d, J = 7.4 Hz); 7.36–7.44
(4H, m); 7.25–7.33 (2H, m); 7.14–7.18 (1H, m); 6.87 (1H, d, J = 8.6 Hz); 5.87
(1H, d, J = 5.7 Hz); 4.64 (1H, d, J = 2.3 Hz); 4.35 (2H, q, J = 7.2 Hz); 3.55–3.58
(1H, m); 3.21–3.24 (1H, m); 2.42–2.45 (1H, m); 1.93–1.96 (1H, m); 1.49–1.57
(4H, m); 1.32–1.44 (3H, m); NMR (100 MHz, TMS, CDCl3) d: 142.1, 140.4, 139.4,
134.8, 128.3, 128.1, 127.3, 127.2, 126.2, 124.9, 122.6, 122.1, 118.1, 115.1, 114.9,
109.1, 107.8 (aromatic C); 72.7, 61.9, 59.9, 39.0, 37.3, 24.5, 19.3, 13.9 (aliphatic
C); m/z = 383 (M+H), positive mode; Anal. Calcd for C26H26N2O: C, 81.64; H,
6.85; N, 7.32. Found: C, 81.68; H, 6.89; N, 7.22.