CuI/La(OTf)3 catalyzed, one-pot synthesis of isomeric ellipticine derivatives in ionic liquid

Article abstract of DOI:10.1016/j.tet.2010.03.095

An efficient method for one-pot synthesis of isomeric ellipticine derivatives through CuI/La(OTf)₃ catalyzed sequential inter/intramolecular cyclization of substituted alkynes with imines followed by aromatization is reported in good to excelle

Full text of DOI:10.1016/j.tet.2010.03.095

Tetrahedron 66 (2010) 4218–4222
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
CuI/La(OTf)3 catalyzed, one-pot synthesis of isomeric ellipticine derivatives
in ionic liquid
*
Vikram Gaddam, Subburethinam Ramesh, Rajagopal Nagarajan
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for one-pot synthesis of isomeric ellipticine derivatives through CuI/La(OTf)3 cata-
lyzed sequential inter/intramolecular cyclization of substituted alkynes with imines followed by aro-
matization is reported in good to excellent yields.
Received 24 February 2010
Received in revised form 24 March 2010
Accepted 25 March 2010
Available online 2 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Copper catalysis
Ionic liquid
Isomeric ellipticine
Lanthanum triflate
1. Introduction
Still, general and facile synthetic approaches are required to obtain
analogues for pharmacological evaluation.
Ellipticine and its analogues have received a vast amount of at-
tention because of their anticancer properties due to interaction with
DNA. Its derivatives exhibit promising results in the treatment of
osteolytic breast cancer metastases, kidney sarcoma, brain tumours
and myeloblastic leukemia.1 The main reason for the interest in
ellipticine and its derivatives for clinical purposes is their high effi-
ciency against several types of cancer, limited toxic side effects and
complete lack of haematological toxicity.2 Recently, it was demon-
strated that ellipticine covalently bindsto DNA in vitro and invivo after
being enzymatically activated with cytochrome P450 or peroxidases.3
Thus, the development of efficient and general methods for the syn-
thesis of this class of compounds has received much attention.4 Sim-
ilarly, the structurally related aryl- and heteroaryl annulated
carbazoles have also received considerable synthetic attention.4,5
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 and fused with other
biologically important molecules.6 Although variety of reports
available for synthesis, most of these methods required harsh re-
action conditions and large number of steps involved for prepara-
tion of requisite starting materials. The synthesis of these
compounds with different substituents at specific locations starting
from easily available materials is far from being well established.
The numerous advantages of transition metals7 and copper
catalysts make them highly attractive for chemical synthesis from
environmental and economic points of view. Copper(I) iodide is an
inexpensive, nontoxic, insensitive catalyst to air in comparison to
other transition metals, such as Pd, Pt, Ru and Au. Therefore, Cu
catalyzed cyclization has been well accepted as a convenient tool
for the synthesis of heterocycles.8
Herein, we report a straightforward CuI/La(OTf)3 catalyzed
tandem reaction for the efficient synthesis of isoellipticine de-
rivatives in ionic liquid [Bmim][BF4]. Ionic liquids are increasingly
used as reaction media in organic synthesis as they offer a wide
range of advantages over classical organic solvents. [Bmim][BF4]
has been exploited as an efficient Lewis acid promoter in various
organic transformations.9 To the best of our knowledge there is no
report available for the preparation of isomeric ellipticine de-
rivatives under copper catalysis.
2. Results and discussion
The reaction of imine derived from 1c (2.0 mmol) and 2a
(2.0 mmol) with phenylacetylene (1.0 mmol) in the presence of CuI/
La(OTf)3 in [Bmim][BF4] afforded 4c along with the side product
4ca. One equivalent of imine underwent the cyclization with phe-
nylacetylene to dihydropyridocarbazole, which further aromatized
to the product 4c (another equivalent of imine acted as a hydrogen
acceptor and underwent reductive amination, i.e., 4ca).
* Corresponding author. E-mail address: rnsc@uohyd.ernet.in (R. Nagarajan).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.095

V. Gaddam et al. / Tetrahedron 66 (2010) 4218–4222
4219
The experimental results are summarized in Table 1. Initially the
Table 2
Synthesisofisomericellipticinederivativeswithdifferentsubstitutedaldehydes(2a–k)
reaction was performed in CH3CN with BF3–OEt2 as a catalyst at
reflux temperature (Table 1, entry 1). In the absence of CuI
(10 mol %), only imine formation was observed. In the presence of
10 mol % of CuI the desired product 4c was obtained with 40% yield
after 24 h reflux in CH3CN (entry 2).
Table 1
Synthesis of isomeric ellipticine derivatives
Entry
Aldehydes
Products
Yield (%)
1
93
Entry
Catalyst
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
BF3–OEt2 (20 mol %)
24
24
24
12
12
12
12
8
8
8
10
12
8
8
8
6
4
4
6
6
d
CuI/BF3–OEt2 (20 mol %)
CuI/CF3–COOH (20 mol %)
CuI/InCl3 (20 mol %)
CuI/In(OTf)3 (10 mol %)
CuI/Ag(OTf) (10 mol %)
CuI/Cu(OTf)2 (10 mol %)
CuI/Sc(OTf)3 (10 mol %)
CuI/Yb(OTf)3 (10 mol %)
CuI/La(OTf)3 (10 mol %)
CuBr/La(OTf)3 (10 mol %)
CuCl/La(OTf)3 (10 mol %)
CuI/La(OTf)3 (10 mol %)/THF
CuI/La(OTf)3 (10 mol %)/Toluene
CuI/La(OTf)3 (10 mol %)/DMSOb
CuI/La(OTf)3 (10 mol %)/[Bmim][Cl]
CuI/La(OTf)3 (10 mol %)/[Bmim][BF4]
CuI/La(OTf)3 (10 mol %)/[Bmim][PF6]
CuI(10 mol %)/[Bmim][BF4]
CuI(30 mol %)/[Bmim][BF4]
40
42
70
75
52
72
83
82
85
62
51
72
75
73
88
93
90
60
62
2
86
9
10
11
12
13
14
15
16
17
18
19
20
3
85
a
Yield refers to column purified product. For the entries 1–12, acetonitrile was
used as a solvent. For the entries 13 and 14 reflux temperature of the corresponding
solvent was maintained.
4
82
b
Temperature was maintained at 100 ꢁC and above the temperature, yield was
low. For the entries 16–20, 1.0 mL of ionic liquid was used. In all entries, catalyst
mol % was calculated relative to phenylacetylene.
Therefore CuI is necessary to activate the triple bond. A series of
different Lewis and Brønsted acids were investigated to improve
the reaction yield. Interestingly, when InCl3 was used as a Lewis
acid, yield was randomly increased to 70% in 12 h (entry 4). The use
of Cu(OTf)2 and In(OTf)3 increased the reaction yield further (entry
5 and 7) and transition metal triflates, such as Scandium triflate,
Ytterbium triflate and Lanthanum triflate also furnished the re-
action in good yield (entry 8–10). All the three triflates were similar
in reactivity in terms of reaction yield.
5
6
95
91
However we preferred La(OTf)3 for further optimization since it
is cheaper and also stable to moisture. We have examined the
catalytic activity of CuI, CuBr and CuCl (entry 11 and 12) and among
them CuI was found to be efficient. Several solvents like, THF,
DMSO, toluene and CH3CN were screened, of which CH3CN found to
be better (entry 13–15). Interestingly, when acetonitrile was
replaced by [Bmim][Cl], the yield increased to 88% (entry 16). The
yield further improved by replacing the counter ion [Clꢀ] with [BF4ꢀ]
(entry 17). We also tried the reaction without using La(OTf)3 and it
gave only 60% yield (entry 19). This indicates that the reaction can
proceed without using La(OTf)3, however CuI is essential. Finally
the optimal reaction conditions for this reaction is as follows:
a mixture of CuI (10 mol %) and La(OTf)3 (10 mol %) as catalysts in
[Bmim][BF4] at 100 ꢁC for 4 h (entry 17). The crystal structures of
both 4c and 4ca were confirmed by single crystal X-ray analysis.10
Having optimized the reaction conditions, the generality of the
reaction with CuI/La(OTf)3 in [Bmim][BF4] with different
substituted aldehydes was examined (Table 2). Substituents having
7
96
8
82
(continued on next page)

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V. Gaddam et al. / Tetrahedron 66 (2010) 4218–4222
Table 2 (continued)
Entry Aldehydes
Table 3
Reactions of substituted aldehydes (2ab–ag) in intramolecular cyclization
Products
Yield (%)
9
80
Entry
1
Aldehydes
Products
Yield (%)
85
10
92
2
3
4
5
6
84
80
96
93
84
11
65
an electron poor (5b–d) or electron rich (5e–g) or heteroaromatic
group (5k) gave the desired products in good to excellent yields.
Even in the case of strong electron deficient 4-fluorobenzaldehyde
(2b) also gave 5b with 86% yield (Table 2, entry 2). Electron rich
aldehyde, such as 2,4,6-trimethyl benzaldehyde (2g) produced
highest yield (96%) in this intermolecular cyclization (entry 7). Pi-
peronal (2h), which has the powerful aroma therapeutic quality,
was also participated in this reaction, gave 82% yield (entry 8).
When we used 1-napthaldehyde (2i) in this reaction furnished 80%
yield (entry 9). Saturated aldehyde, cyclohexanal (2j) produced 92%
yield within 3 h (entry 10). But in the case of heteroaromatic al-
dehyde, such as 2-chloro-quinoline-3-carboxyaldehyde (2k) fur-
nished only 65% yield (entry 11). Substrates bearing functional
groups, such as F, Cl, Br and OCH3 were tolerated. This made pos-
sible the further derivatization of the products. Product 5g was also
confirmed by single crystal X-ray analysis.10
substituted aldehyde (2ad) gave 80% yield (Table 3, entry 3),
whereas methyl substituted aldehyde (2ae) produced 96% yield
(entry 4). The reaction of O-propargylated naphthaldehyde (2ag)
with 9-ethyl-3-aminocarbazole in the presence of Cu/La(OTf)3 in
ionic liquid afforded 6g with 84% yield (entry 6). The products 6b
and 6g were also confirmed by single crystal X-ray analysis.10
Having established the suitable reaction conditions, we ex-
plored the scope and generality of the methodology with
substituted alkynes and the results are summarized in Table 4. Yield
of 75% was obtained with diphenylacetylene (7b). Substitution on
the other side of the alkyne carbon with electron donating groups
(7c–e) proceeds with excellent yields. Even with trimethylsilyl
acetylene (2.0 equiv), the reaction proceeded smoothly with 72%
yield (7g). As silyl end groups on the alkynes are lost upon the
work-up, access to the unfunctionalized products were obtained
easily.11 Crystal structures of 7b, 7d, 7e and 7f were achieved in
order to confirm their structures.10
An intramolecular version of this reaction could provide a valu-
able route to isoellipticine fused with dihydro chromene de-
rivatives. We have carried out the reaction of O-propargylated
salicylaldehyde (2aa) with 1c in the presence of CuI/La(OTf)3 in
ionic liquid (Scheme 1). Surprisingly the reaction was completed
within one hour in 95% yield. In 1H NMR spectrum of 6a, un-
expected two singlets at
d 7.93 and 8.87 was observed and after
careful analysis, we identified the cyclization occurred through
second position of the carbazole ring unlike in the intermolecular
case, where it happened through fourth position of the carbazole
ring. The structure was also further proved by single crystal X-ray
analysis.10
The copper catalyzed cyclization of substituted aminocarbazoles
(1a–i) under the optimized conditions were carried out and the
results are summarized in Table 5. In most cases, the corresponding
products 4a–i were obtained in excellent yields. However 1i has the
slower rate of the reaction and the corresponding product 4i was
obtained in only 72% yield. This may be due to the steric hindrance
caused by two methyl substituents (Table 5, 4i).
We have also examined the reaction of 3,6-diaminocarbazole
with benzaldehyde, phenylacetylene and 2aa under the same re-
action conditions (Scheme 2). The intermolecular reaction
Scheme 1. Synthesis of isoellipticine derivative fused with chromene.
With substituted O-propargyl aldehydes (2ab–ag), reaction
proceeded smoothly under the optimized reaction conditions and
the results are summarized in Table 3. In all the cases, the corre-
sponding intramolecular cyclization products (6b–g) were
obtained in excellent yields (80–96%) and the cyclization occurs
through the fourth position of the carbazole ring. Bromo

V. Gaddam et al. / Tetrahedron 66 (2010) 4218–4222
4221
Table 4
Table 5
Synthesis of isomeric ellipticine derivatives from different substituted alkynes
Synthesis of isomeric ellipticine derivatives with substituted aminocarbazoles (1a–i)
(3a–g)
Entry
1
R1
H
R2
H
Products
Yield (%)
93
2
3
H
H
Ph
75
90
CH3
4
H
n-C3H7
91
5
H
n-C4H9
94
Scheme 2. Synthesis of bis products.
6
7
OCH3
95
72
Scheme 3. Expected mechanism of the reaction.
including the mechanistic study are being conducted in our
laboratory.
proceeded well and furnished the corresponding product in 62%
yield. Product 8a was confirmed by single crystal analysis.10 The
intramolecular pathway of diaminocarbazole gave 76% yield and
there is no monocyclized product was observed.
3. Experimental section
3.1. General procedure
Though the mechanism of copper catalyzed cyclization is well
known,12 scanty reports are available for the use of alkyne as
a dienophile.13 When a terminal alkyne was used, the copper cat-
alyzed reaction can be proceeded through a reported mechanism14
but in case of disubstituted alkynes, the reported mechanism may
not be suitable since there is no terminal hydrogen. According to
HSAB theory hard Lewis acid, La3þ coordinates the hard Lewis base
site of nitrogen lone pair and increases the electron deficiency of
the imine, cyclization followed by aromatization (Scheme 3).
In summary, we described for the first time the synthesis of
isomeric ellipticine derivatives with inter and intramolecular cy-
clization catalyzed by CuI/La(OTf)3. Further studies in this area
In a round bottom flask equipped with a magnetic stirring bar,
2.0 mmol of aminocarbazole, 2.0 mmol of aldehyde, 1.0 mmol of
alkyne in 1.0 mL of [Bmim][BF4] ionic liquid, was added 10 mol % of
La(OTf)3 and 10 mol % of CuI. Reaction mixture was stirred at 100 ꢁC
for appropriate time. After completion of the reaction, as indicated
by the TLC, water (20 mL) was added to the crude reaction mass.
Then aqueous layer was extracted with dichloromethane
(3ꢂ20 mL) and the combined organic layers were dried over
Na2SO4, filtered and concentrated under the reduced pressure.

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V. Gaddam et al. / Tetrahedron 66 (2010) 4218–4222
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Product was purified by column chromatography on silica gel (el-
uent: hexane/ethyl acetate) afforded the corresponding products.
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(30% EtOAc/hexane): 0.40; IR (KBr): 3395, 3057, 1556, 1412, 796,
625 cmꢀ1; 1H NMR (400 MHz, CDCl3, TMS)
d: 8.68 (1H, s); 8.28 (3H,
d, J¼7.8 Hz); 7.95 (1H, s); 7.81 (1H, d, J¼8.0 Hz); 7.45–7.61 (8H, m);
7.38 (1H, d, J¼7.2 Hz); 7.22 (1H, t, J¼7.8 Hz); 6.70 (1H, t, J¼7.6 Hz);
6.02 (1H, d, J¼7.7 Hz); 13C NMR (100 MHz, CDCl3, TMS)
d: 153.3,
147.0, 146.8, 142.8, 139.7, 138.7, 138.4, 129.7, 129.2, 129.0, 128.9,
128.3,127.4,124.9,124.2,123.9,122.5,121.3,121.0,119.2,116.5,115.0,
110.3 (aromatic C); m/z¼371 (MþHþ), positive mode. Anal. Calcd
for C27H18N2: C, 87.54; H, 4.90; N, 7.56%. Found: C, 87.45; H, 4.88;
N, 7.61%.
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(6a). Mp 202 ꢁC; Rf (10% EtOAc/hexane)¼0.59; IR (KBr): 3045,1602,
1224, 819, 738, 480 cmꢀ1 1H NMR (400 MHz, CDCl3, TMS)
; d: 8.87
(1H, s); 8.58 (1H, d, J¼8.0 Hz); 8.29 (1H, d, J¼7.2 Hz); 7.93 (1H, s);
7.53–7.61 (2H, m); 7.33–7.40 (2H, m); 7.30 (1H, t, J¼7.8 Hz); 7.23 (1H,
t, J¼7.6 Hz); 7.07 (1H, d, J¼7.8 Hz); 5.40 (2H, s, OCH2); 4.37 (2H, q,
J¼8.0 Hz, N–CH2CH3); 1.49 (3H, t, J¼7.8 Hz, N–CH2CH3); 13C NMR
(100 MHz, CDCl3, TMS) d: 157.2,146.1,142.8,142.7,139.7,131.2,129.9,
128.2,127.8,126.5,125.2,124.4,123.8,122.7,122.5,121.6,120.0,119.2,
117.3,108.3,102.3 (aromatic C), 68.8, 37.7,13.3 (aliphatic C); m/z¼351
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Acknowledgements
We gratefully acknowledge DST for financial assistance (Project
number: SR/S1/OC-70/2008). GV and SR thank CSIR for providing
Senior and Junior Research Fellowships respectively.
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Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.03.095.
10. See Supplementary data.
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