Palladium-catalyzed intramolecular γ-lactam formation of an aryl halide and an enolate: Synthesis of isoindolobenzazepine alkaloids, lennoxamine, 13-deoxychilenine, and chilenine

Article abstract of DOI:10.1016/j.tetlet.2005.08.025

A facile synthetic path to isoindolobenzazepine alkaloids, lennoxamine, 13-deoxychilenine, and chilenine, was established by employing a palladium-catalyzed intramolecular α-arylation of the ketone, as the key step.

Full text of DOI:10.1016/j.tetlet.2005.08.025

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6823–6825
Palladium-catalyzed intramolecular c-lactam formation
of an aryl halide and an enolate: synthesis of
isoindolobenzazepine alkaloids, lennoxamine,
13-deoxychilenine, and chilenine
Toshio Honda* and Yoshiaki Sakamaki
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41, Shinagawa, Tokyo 142-8501, Japan
Received 19 July 2005; revised 29 July 2005; accepted 4August 2005
Available online 19 August 2005
Abstract—A facile synthetic path to isoindolobenzazepine alkaloids, lennoxamine, 13-deoxychilenine, and chilenine, was established
by employing a palladium-catalyzed intramolecular a-arylation of the ketone, as the key step.
Ó 2005 Elsevier Ltd. All rights reserved.
Palladium-catalyzed intramolecular a-arylation of
ketones, esters, and amides is recognized as one of the
most promising procedures for constructing polycyclic
compounds, including heterocycles.1 Recently, we have
demonstrated the versatility and utility of the methodol-
ogy in the synthesis of isoquinoline alkaloids, chellyrine,
and latifine, in which d-lactam formation was involved,
as a key step.2 As part of our continuing exploration
of palladium-catalyzed intramolecular carbon–carbon
bond formation of aryl halides and enolates, we were
interested in the synthesis of natural isoindolobenzaze-
pine alkaloids, lennoxamine, 13-deoxychilenine, and
chilenine, aiming at the construction of an iso-
indolobenzazepine ring by this reaction.
O
O
O
O
O
O
N
N
OMe
OMe
OMe
OMe
O
R
2. 13-Deoxychilenine: R = H
3. Chilenine: R = OH
1. Lennoxamine
Figure 1. Structures of isoindolobenzazepine alkaloids.
Our synthesis of isoindolobenzazepine alkaloids starts
from Schotten–Baumann acylation of the known
benzazepinone derivative 48 with 6-bromo-2,3-di-
methoxybenzoyl chloride 59 to afford the corresponding
amide 6 in 91% yield. With screening of a variety of
reaction conditions, such as the species of palladium cat-
alysts, ligands, and solvents, for a palladium-catalyzed
intramolecular a-arylation of 6, we found proper reac-
tion conditions for obtaining the desired cyclization
product in reasonable yield, as follows (Scheme 1).
Lennoxamine 1, 13-deoxychilenine 2, and chilenine 3
were isolated from Berbelis darwinii,3 Berbelis actinacan-
tha,4 and Berbelis empetrifolia5 as racemic forms, respec-
tively. Since these alkaloids have relatively simple
structural features, a number of total syntheses of 16
and 36c,d,7 have been achieved by application of newly
developed synthetic strategy and methodology. How-
ever, the synthesis of 2 has not been reported yet
(Fig. 1).
The Pd-catalyzed intramolecular coupling reaction of 6
in the presence of 5 mol % of Pd2(dba)3ÆCHCl3,
10 mol % of ( )-BINAP, and 1.5 equiv of KOt-Bu in
refluxing dioxane proceeded smoothly to give the de-
sired lactam 2 in 65% yield, together with a debromo-
compound (18%). The spectroscopic data10 of the syn-
thesized compound 2, mp 156–157 °C (lit.,4 mp 156–
157 °C), were identical with those reported in the
literature.4
Keywords: Lennoxamine; 13-Deoxychilenine; Chilenine; Palladium-
catalyzed intramolecular a-arylation; Isoindolobenzazepine alkaloid.
*
Corresponding author. Tel.: +81 3 5498 5791; fax: +81 3 3787
0036; e-mail: honda@hoshi.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.025

6824
T. Honda, Y. Sakamaki / Tetrahedron Letters 46 (2005) 6823–6825
O
O
O
O
a
N
NH
O
OMe
OMe
O
Br
O
4
6
O
O
O
b
N
c
OMe
O
OMe
2
O
O
O
O
O
O
N
N
d
OMe
OMe
OMe
OMe
HO
7
1
Scheme 1. Reagents and conditions: (a) 6-bromo-2,3-dimethoxybenzoyl chloride 5, aq NaHCO3, Et2O, 0 °C (91%); (b) Pd2(dba)3/CHCl3, BINAP,
KOt-Bu, dioxane, reflux (65%); (c) NaBH4, EtOH, rt; (d) Et3SiH, BF3/OEt2, CH2Cl2, rt (67% from 2).
Thus, we were able to establish the facile first synthesis
of 13-deoxychilenine in short steps. Although the cou-
pling reaction was carried out in the presence of chiral
ligand (S)-BINAP under the same reaction conditions
as above, directed at its chiral synthesis, the product
was found to be racemate, probably due to the presence
of the easily enolizable benzylic ketone in the cyclization
product 2.10
palladium-catalyzed intramolecular a-arylation of the
ketone 6 as the key step. The strategy developed here
provides a further useful example of the palladium-cat-
alyzed coupling reaction of aryl halides with enolates,
and seems to be widely applicable to the synthesis of a
number of biologically active compounds, including nat-
ural products.
In order to establish the synthesis of lennoxamine, the
13-deoxychilenine 2 was converted to the alcohol 7 on
reduction with sodium borohydride. Further reduction
of 7 with triethylsilane in the presence of boron trifluo-
ride etherate furnished lennoxamine 1 in 67% yield from
2. The spectroscopic data of 1, mp 228–229 °C (lit.,11 mp
228–229 °C), were identical with those reported in the
literature6d,10 (Scheme 2).
Acknowledgments
This work was supported in part by a grant from the
Ministry of Education, Culture, Sports, Science, and
Technology of Japan.
References and notes
Synthesis of chilenine 3 was also achieved by direct oxi-
dation of 13-deoxychilenine 2 with Davisꢀ reagent [race-
mic 3-phenyl-2-(phenylsulfonyl)oxaziridine] in the
presence of sodium hexamethyldisilazide, as the base,
in 95% yield. Again, the spectroscopic data of 3, mp
157–158 °C (lit.,6d mp 157–158 °C), were identical with
those reported in the literature.6d
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In summary, we were able to establish the concise syn-
thesis of isoindolobenzazepine alkaloids, lennoxamine
1, 13-deoxychilenine 2, and chilenine 3, by employing
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O
O
O
O
O
O
N
N
a
OMe
OMe
OMe
OMe
HO
O
O
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3
Scheme 2. Reagents and conditions: (a) Davis reagent (4equiv),
NaHMDS, THF, À78 °C to rt (95%).

T. Honda, Y. Sakamaki / Tetrahedron Letters 46 (2005) 6823–6825
6825
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1
CDCl3) d: 3.00 (ddd, 1H), 3.39 (ddd, 1H), 3.57 (ddd, 1H),
3.83 (s, 3H), 3.92 (s, 3H), 4.15 (ddd, 1H), 4.72 (s, 1H), 5.93
(d, 1H), 5.95 (d, 1H), 6.65 (s, 1H), 6.74(s, 1H), 6.98 (d,
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