Intramolecular Heck reaction of methylenephthalimidine derivatives: A simple route to lennoxamine and chilenine

Article abstract of DOI:10.1016/j.tetlet.2003.09.069

A new concise route to the key intermediate for isoindolobenazepine alkaloids, lennoxamine and chilenine, was developed using amine and keto-ester condensation followed by Heck reaction.

Full text of DOI:10.1016/j.tetlet.2003.09.069

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8207–8209
Intramolecular Heck reaction of methylenephthalimidine
derivatives: a simple route to lennoxamine and chilenine
Guncheol Kim,* Jin Hee Kim, Won-jeong Kim and Yeon Ah Kim
Department of Chemistry, College of Natural Sciences, Chungnam National University, Daejon 305-764, Republic of Korea
Received 27 August 2003; revised 9 September 2003; accepted 11 September 2003
Abstract—A new concise route to the key intermediate for isoindolobenazepine alkaloids, lennoxamine and chilenine, was
developed using amine and keto-ester condensation followed by Heck reaction.
© 2003 Elsevier Ltd. All rights reserved.
Isoindolobenazepine alkaloids lennoxamine
1
and
cessfully.2f Herein we report an alternative simple route
to the known key intermediate 32e,j for the two products
via intramolecular Heck reaction (Fig. 1).
chilenine 2, isolated from the plants of the Chilean
Berberis species, are a new class of alkaloids belonging
to the aporhoedane series.1 Although these alkaloids do
not have important biological activities, their unique
structural feature, five- and seven-membered rings fused
with aromatic moiety has drawn the synthetic interest
of many groups.2 The formation of isoindolobe-
nazepine ring has been accomplished mainly by various
cyclization reactions including trans-annulation. Several
ring expansion reactions have been also applied suc-
In the application of Heck reaction for the benzazepine
alkaloids, we considered that intermediate 3 could be
prepared by the reaction from the precursor 4, which
would be readily obtained by the one-pot condensation
reaction of two compounds,3 2-iodoarylamine 5 and
aryl keto-ester 6 (Scheme 1).
Preliminary experiments for cyclization have been car-
ried out on the simple molecules employing a conven-
tional Heck type reaction condition, Pd(OAc)2 in DMF
containing K2CO3 and LiCl. Methylenephthalimidine
precursors 7, which have been prepared by reaction of
2-acetylbenzoic acid with the corresponding 2-haloaryl-
amines in good yields, were heated in DMF containing
the reagents at 120°C for 12–16 h. Tetracyclic amides 8
with 5–7-membered rings were made in moderate to
satisfactory yields, respectively (Scheme 2).
Figure 1.
Scheme 1.
Keywords: Heck reaction; lennoxamine; chilenine; methylenephthalimide.
* Corresponding author. Tel.: 082-42-821-5475; fax: 082-42-823-1360; e-mail: guncheol@cnu.ac.kr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.069

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G. Kim et al. / Tetrahedron Letters 44 (2003) 8207–8209
Scheme 2.
Scheme 3.
Table 1. Heck reaction conditions for the cyclization of 3
Entry
Pd(OAc)2 (equiv.)
Conditions
Yielda (%) of
3
10
1
2
3
4
5
6
0.1
0.1
0.1
0.1
0.1
0.12
nBu4NCl (1 equiv.), NaHCO3 (2.5 equiv.), DMF, 110°C, 16 h
nBu4NCl (1 equiv.), NaHCO3 (2.5 equiv.), 3A MS, CH3CN, reflux, 16 h
nBu4NCl (2 equiv.), KOAc (5.5 equiv.), 3A MS, DMF, 110°C, 18 h
nBu4NCl (2 equiv.), KOAc (5.5 equiv.), DMF, 110°C, 18 h
PPh3 (0.2 equiv.), Et3N (2 equiv.), CH3CN, reflux, 18.5 h
Et3N (3 equiv.), DMF, 110°C, 120 h
50
28
34
54
47
34
a Isolated yield.
With these results, we were prompted to pursue the
synthesis of 3. Compound 9 was prepared readily by
slight modification of the known procedure,4 and
hydration of 9 under HgO/H2SO4 provided 6 in 73%
yield. The intermediate 5 was prepared as reported
from the commercialized 3,4-methylenedioxyphenethyl-
amine.5 The condensation reaction of 5 and 6 under
refluxing toluene provided 58% yield of 4 (Scheme 3).
In summary, we developed a new concise route to the
key intermediate for isoindolobenazepine alkaloids
using amine and keto-ester condensation followed by
Heck reaction.
Acknowledgements
This work was supported by grant (R01-2000-000-
00048-0) from the Basic Research Program of Korea
Science and Engineering Foundation, and we appreci-
ate Center for Research Facility, CNU for the permis-
sion of using NMR spectrometer.
Finally, cyclization of 4 to 3 was attempted under the
same condition used above. However, the desired com-
pound 3 was obtained in only 10% yield with a few
unidentified by-products. In order to obtain the opti-
mum yield of 3, we used several conditions reported for
the Heck type cyclization6 as shown in Table 1. The use
of nBu4NCl in the reaction mixture was found to be
critical for the endo-type cyclization to provide 37 with
recovered starting material. The yields were from 28 to
54% (entries 1–4). Other conditions without the reagent
yielded only 108 in 34 or 47% yield (entries 5 and 6).
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