A new route to the synthesis of ellipticine quinone from isatin

Article abstract of DOI:10.1016/j.tetlet.2013.12.098

1-(2-Oxo-2-(pyridin-4-yl)ethyl)indoline-2,3-dione can be prepared and converted by treatment with sodium hydroxide into 2-isonicotinoyl-1H-indole-3- carboxylic acid as a key intermediate which can be transformed into ellipticine quinone in a two step sequ

Full text of DOI:10.1016/j.tetlet.2013.12.098

Tetrahedron Letters 55 (2014) 1104–1106
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new route to the synthesis of ellipticine quinone from isatin
⇑
Nagarajan Ramkumar, 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:
1-(2-Oxo-2-(pyridin-4-yl)ethyl)indoline-2,3-dione can be prepared and converted by treatment with
sodium hydroxide into 2-isonicotinoyl-1H-indole-3-carboxylic acid as a key intermediate which can be
transformed into ellipticine quinone in a two step sequence.
Received 20 November 2013
Revised 25 December 2013
Accepted 26 December 2013
Available online 3 January 2014
Ó 2014 Published by Elsevier Ltd.
Keywords:
Alkaloids
Rearrangement
o-Lithiation
Total synthesis
Ellipticine quinone
Pyrido[4,3-b]carbazole1 containing alkaloids comprise a group
of naturally occurring biologically active compounds and have at-
tracted a broad interest in chemistry, biology, and pharmacology.
Ellipticine 1 (5,11-dimethyl-6H-pyrido[4,3-b]carbazole, Fig. 1)2
and its congeners are well-known for their biological activities
such as anticancer,3 antineoplastic4 and their use of treatment
for myeloblastic leukemia, advanced breast cancer, and solid
O
H3C
N
N
N
H
N
H
O
CH3
Ellipticine 1
Ellipticine quinone 2
tumors.5 Ellipticine quinone
2
(5H-pyrido[4,3-b]carbazole-
Figure 1. Structures of ellipticine (1) and ellipticine quinone (2).
5,11(6H)-dione, Fig. 1)6 is an important synthetic intermediate
and it can easily be converted into ellipticine 1 by known
methods.7
to give 2-acylindole-3-carboxylic acids as a result of the facile
opening of the five-membered isatin ring in aqueous alkali solu-
tions, super basic media, and alcoholic solutions of sodium alkox-
ides.9–12
Condensation of ortho-aminophenylcarbonyl compounds with
a
-halomethylketones is a versatile route for the synthesis of in-
The indoledione-indole rearrangement8–12 is one of the best
methods for the synthesis of 2-acylindole-3-carboxylic acids since
it is atom economic and requires a simple base to promote the
reaction. It can be described as the isomerization of 1-[2-oxoalky-
l(aryl or heteroaryl)]indole-2,3-diones into 2-acylindole-3-carbox-
ylic acids.
doles possessing an acyl group at C(2).8 ortho-Aminophenylglyoxy-
lic acids are readily generated in situ by the effect of an alkali
(usually NaOH) on isatins. The reaction of ortho-aminophenylgly-
oxylic acids with
a-halomethylketones can be formulated into a
general synthesis for 2-acylindole-3-carboxylic acids and their N-
alkyl derivatives.9 However, because of the low reactivity of the
salts with respect to N-alkylation, this reaction does not occur
either in aprotic solvents at increased temperature or in strongly
basic media or with phase transfer catalysis.10
Isatin (indoline-2,3-dione) 3 is commercially available, a multi-
functional heterocycle containing nitrogen atom whose behavior in
alkylation reactions is strongly based on the reaction conditions
and nature of the alkylating agents used.11 Isatin may react with
Directed ortho-metallation13 (DoM) plays a vital role in the
modern organic synthesis. Syntheses of various heterocyclic qui-
nones are reported by using tandem metallation in situ cyclization
of (het)arylpyridylketones bearing an alkyl carboxylate or a lithium
carboxylate group at a remote position from the pyridine ring.14 To
the best of our knowledge, there are no reports concerning the syn-
thesis of ellipticine quinone from isatin until now. Our interest of
using 1-(2-oxo-2-(pyridin-4-yl)ethyl)indoline-2,3-dione 9 as syn-
thetic precursor for the synthesis of ellipticine quinone is described
in this Letter.
a-halomethylketones at the b-CO or NH group. If the reaction pro-
ceeds with N-alkylation, the products formed smoothly isomerize
Our synthetic approach for the synthesis of ellipticine quinone
is outlined in Scheme 1. We envisioned that ketone 9 can be
⇑
Corresponding author.
E-mail address: rnsc@uohyd.ernet.in (R. Nagarajan).
0040-4039/$ - see front matter Ó 2014 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2013.12.098

N. Ramkumar, R. Nagarajan / Tetrahedron Letters 55 (2014) 1104–1106
1105
CO2Na
synthesized from isatin using appropriate N-alkylating reagents
which can easily be converted to 2-isonicotinoyl-1H-indole-3-car-
boxylic acid 11 under basic condition via indoledione-indole rear-
rangement. Finally, ellipticine quinone 2 could be obtained from 11
by exploiting ortho-lithiation strategy (Scheme 2).
20% aq.NaOH
O
N
N
9
EtOH, reflux, 8 h
H
O
10
The first key step in the synthesis of ellipticine quinone is the
synthesis of 9 from isatin 3 using various alkylating reagents
shown in Figure 2 which were prepared from known procedures.15
We initially performed reaction between sodium 2-(2-aminophe-
nyl)-2-oxoacetate 7 (derived from isatin 3 upon treatment with
NaOH/MeOH) and 2-bromo-1-(pyridin-4-yl)ethanone hydrobro-
mide 4 in DMF at 70 °C for 5 h affording 9 in 17% yield. Many at-
tempts to increase yield of 9 under various conditions were less
than satisfactory due to low reactivity of salts 4 and 7. However,
treatment of 3 with other alkylating reagents such as 2-bromo-1-
(pyridin-4-yl)ethanol 5 or 4-(oxiran-2-yl)pyridine 6 in NaH/DMF
CO2H
N
N
N
H
N
H
O
12
O
11
Scheme 3. Indoledione-indole rearrangement of 9 to carboxylic acid (11).
gave
1-(2-hydroxy-2-(pyridin-4-yl)ethyl)indoline-2,3-dione
CO2Et
N
SOCl2, EtOH
11
O
CO2H
N
reflux, 3 h,92 %
N
N
DoM
H
O
13
N
H
N
H
O
O
O
N
LiHMDS
TMEDA
THF, -78 o
3 h, 68 %
indoledione-indole
rearrangement
C
N
H
O
O
2
O
N-alkylation
O
N
Scheme
bis(trimethylsilyl)azanide).
4. Synthesis
of
ellipticine
quinone
(2).
(LiHMDS = lithium
O
O
N
H
N
hydrochloride 8 in 78% yield which was then oxidized to 9 by
IBX/DMSO (Scheme 3).
Scheme 1. Retrosynthetic analysis of ellipticine quinone (2).
The next key step is the rearrangement of ketone 9 to carboxylic
acid 11. Hydrolysis of compound 9 using 20% aqueous NaOH in
ethanol at reflux for 8 h afforded 11 through an intermediate 10
along with easily separable decarboxylated product 12 in 76%
and 24% yields respectively (Scheme 4).
The key intermediate 11 was subjected to esterification with
ethanol to give corresponding ester 13 in 92% yield. Then we con-
ducted directed ortho-lithiation of 13 by utilizing 5 equiv of
LiHMDS/TMEDA in THF at À78 °C for 3 h producing our target
ellipticine quinone 2 in 68% yield.
O
CO2Na
ii
i
NH2
O
7
O
O
N
O
O
O
N
H
3
9
In summary, we reported a simple and efficient route to the
synthesis of ellipticine quinone (2) from isatin. Key reactions in-
cluded N-alkylation of isatin, indoledione-indole rearrangement,
and directed ortho-lithiation. In addition, this synthetic route
iii
O
N
iv
HO
N
8
may be used as
alkaloids.
a model for similar pyrido[4,3-b]carbazole
N
H Cl
Scheme 2. Synthesis of 1-(2-oxo-2-(pyridin-4-yl)ethyl)indoline-2,3-dione (9).
Reagents and conditions: (i) NaOH, MeOH, reflux, 5 h (ii) 2-bromo-1-(pyridin-4-
yl)ethanone hydrobromide, DMF, 70 °C, 5 h, 19% (iii) NaH, 2-bromo-1-(pyridin-4-
yl)ethanol or 4-(oxiran-2-yl)pyridine, DMF, rt, overnight, 76–81% (iv) IBX, DMSO, rt,
6 h, 84%.
Acknowledgements
We are grateful for the financial support of the DST (Project No:
SR/S1/OC-70/2008). N.R. also thanks CSIR for SRF fellowship and
contingency grant and dedicates this paper to his mentor Prof. R.
Manian, Department of Chemistry, Gobi Arts and Science College,
Tamil Nadu, India.
Br
Br
O
O
OH
Supplementary data
N
H
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.20
13.12.098.
N
N
Br
4
5
6
Figure 2. N-alkylating reagents of isatin (3).

1106
N. Ramkumar, R. Nagarajan / Tetrahedron Letters 55 (2014) 1104–1106
Gribble, G. W.; Fletcher, G. L.; Ketcha, D. M.; Rajopadhye, M. J. Org. Chem. 1989,
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