A concise synthesis of chilenine via a sequential reaction process

Article abstract of DOI:10.1016/j.tetlet.2008.02.057

A new short synthesis of chilenine has been achieved in two steps. The precursor amide was readily prepared by the condensation of the corresponding amine and acid. Treatment of the amide with oxalyl chloride in the presence of AlCl₃ at room te

Full text of DOI:10.1016/j.tetlet.2008.02.057

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Tetrahedron Letters 49 (2008) 2391–2392
A concise synthesis of chilenine via a sequential reaction process
Guncheol Kim *, Philguem Jung, Le Anh Tuan
Department of Chemistry, College of Natural Science, Chungnam National University, Taejon 305-764, Republic of Korea
Received 14 January 2008; revised 9 February 2008; accepted 12 February 2008
Available online 14 February 2008
Abstract
A new short synthesis of chilenine has been achieved in two steps. The precursor amide was readily prepared by the condensation of
the corresponding amine and acid. Treatment of the amide with oxalyl chloride in the presence of AlCl3 at room temperature afforded the
desired product chilenine through sequential Friedel–Crafts acylation, amide cyclization to imide, and intramolecular Friedel–Crafts
type reaction. The synthesis suggests a new potential of oxalyl chloride for a two-carbon synthon.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Chilenine; Oxalyl chloride; Friedel–Crafts reaction; Sequential reaction
One of isoindolobenzazepine alkaloid chilenine 1 has
been isolated from Berberis empetrifolia Lam as a racemic
form (Fig. 1).1 Due to its unique carbonyl–hydroxyl func-
tional groups in the tetracyclic ring, many groups have
shown synthetic interests to suggest several attractive ways
for the ring skeleton as well as total synthesis.2–12
As an extension of our study for exploring successive
ring formation of alkaloids,13–16 herein, we describe a
new sequential process for the synthesis of chilenine by
using oxalyl chloride. The reagent has been known to react
with aroylacetic esters to provide a quinone skeleton under
Friedel–Crafts reaction conditions.17
cyclization (path b), affording intermediate 3, and the sub-
sequent intramolecular Friedel–Crafts type alkylation to
the resulting carbonyl-imide functional group would afford
the desired product 1 in a concise manner (Scheme 1).
The requisite precursor 2 was readily prepared by the
condensation of 3,4-methylenedioxyphenlethyl amine and
2,3-dimethoxybenzoic acid in 73% yield. As a preliminary
study, we wanted to examine up to which step the reaction
would proceed in a pot, and so we added one equivalent of
oxalyl chloride to a solution of 2 in methylene chloride at
room temperature. Surprisingly, we could separate out
the desired product 1, though, in small yield. And we con-
sidered that the reaction could occur sequentially to yield
In the approach, we envisioned that Friedel–Crafts reac-
tion of 2 (path a) would be followed by amide-acyl chloride
O
O
O
O
O
O
N
HN
b
sequential
O
a
OMe
OMe
O
OMe
OMe
a
c
O
b
Cl
O
HO
N
Cl
c
process
O
O
OMe
O
HO
1
2
OMe
O
O
1: Chilenine
OMe
OMe
N
O
Fig. 1.
O
O
3
*
Corresponding author. Tel.: +82 042 821 5475; fax: + 82 042 823 1360.
Scheme 1.
E-mail address: guncheol@cnu.ac.kr (G. Kim).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.057

2392
G. Kim et al. / Tetrahedron Letters 49 (2008) 2391–2392
OMe
O
O
OMe
OMe
HO2C
Cl
O
O
Cl
H
OMe
NHAc
NAc
O
N
O
O
O
O
O
O
O
NH2
EDCI
O
AlCl3, CH2Cl2
20%
4
73%
Cl
2
6
7
O
Scheme 4.
AlCl3, CH2Cl2
rt, 4 h
Cl
O
In conclusion, we have suggested a concise way to iso-
indolobenzapine alkaloid chilenine in two steps. Oxalyl
chloride has been used as a two-carbon synthon and a
source of two carbonyl functional groups in proper
position for the synthesis. Lewis acid AlCl3 has enabled
the three-step process to proceed sequentially, affording
the product in good yield under mild condition.
O
O
O
N
OMe
OMe
HO
O
85%
1
Scheme 2.
Acknowledgments
O
O
OMe
i.
This work was supported by grant (R01-2007-000-
20037-0) from the Basic Research Program of Korea
Science and Engineering Foundation, and we appreciate
the Center for Research Facilities, CNU, for the
permission to NMR.
Cl
O
O
Cl
OMe
O
O
O
N
O
HN
O
H
AlCl3, CH2Cl2
rt, 30 min
OMe
OMe
OMe
65%
O
2
ii. MeOH / Et3N
5
Scheme 3.
References and notes
the final product. Then, we found an optimized condition
which yielded 1 in 85% yield, addition of 10 equiv of oxalyl
chloride to the solution of 2 containing 3 equiv of AlCl3 at
0 °C and stirring the mixture for 4 h at room temperature
(Scheme 2). The spectral data of 1, mp 158–159 °C (lit.,9
mp 157–158 °C), were identical to those reported in the
literature.9
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Although we could finish the synthesis of chilenine 1 in
two steps, it would be worthwhile supporting the proposed
reaction steps by showing the reaction intermediates. When
the reaction was quenched with MeOH and Et3N early in
30 min, we could separate compound 5 in 65% yield
(Scheme 3). We assumed that 5 should be made from an
acyl chloride intermediate obtained through Friedel–Crafts
reaction of 2 with oxalyl chloride (Scheme 1, path a). How-
ever, we could not find intermediate 3, which would be
formed by the next reaction (Scheme 1, path b). It might
be because of the immediate consumption of 3 for the final
step (Scheme 1, path c). Therefore we synthesized com-
pound 6, which has an acetyl group on nitrogen instead
of a dimethoxy-benzoyl group and treated it with oxalyl
chloride under the same condition, and could separate
the tricarbonyl compound 718 in ca. 20% yield (Scheme
4), which is assumed to support path b and path c
suggested in Scheme 1. AlCl3 seemed to act as an efficient
catalyst in each step of the reactions and therefore enable
the process in a sequential manner.
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5395–5398.
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18. 1H NMR (400 MHz, CDCl3): d 1.94 (s, 3H), 2.84 (m, 1H), 3.05 (m,
1H), 3.53 (m, 1H), 4.52 (m, 1H), 5.99 (m, 1H), 6.00 (m, 1H), 6.59 (s,
1H), 6.92 (s, 1H); 13C NMR (100 MHz, CDCl3): d 27.7, 28.9, 37.3,
90.8, 101.5, 105.2, 108.2, 125.8, 127.5, 147.1, 148.8, 152.0, 158.3.