Synthesis of Isoindolobenzo[c]Azepine Skeleton Via Sequential Amidation and Aza-Michael Reaction Followed by Friedel–Crafts Acylation

Full text of DOI:10.1002/bkcs.11582

Communication
DOI: 10.1002/bkcs.11582
BULLETIN OF THE
K. J. Lee and G. Kim
KOREAN CHEMICAL SOCIETY
Synthesis of Isoindolobenzo[c]Azepine Skeleton Via Sequential Amidation
and Aza-Michael Reaction Followed by Friedel–Crafts Acylation
*
Kun Jung Lee and Guncheol Kim
Department of Chemistry, College of Natural Sciences, Chungnam National University, Daejon 305-764,
Republic of Korea. *E-mail: guncheol@cnu.ac.kr
Received July 16, 2018, Accepted August 22, 2018
Keywords: Friedel–Crafts acylation, Amidation, Aza-Michael reaction, Azepine, Polyphosphoric acid
Lennoxamine 1, chilenine 2, and palamine 3 (Figure 1), iso-
lated from Berberis empetrifolia Lam1 and Berberis darwinii
Hook,2 have an isoindolobenzo[d]azepine framework. Synthetic
chemists have focused on the unique core seven- and five-
membered ring systems of this framework despite the weak
biological activities of 1, 2, and 3.3 The analogue isoindolo-
benzo[c]azepine 4, however, has not received much interest,
partly because its related natural products are less abundant.4
As an extension of our azonine and azepine alkaloid synthetic
study,5 herein we suggest a practical synthetic route for the struc-
ture through a sequential process. The amidation of benzoyl ester
6 with benzylamine 7 and the aza-Michael reaction of the cou-
pling intermediate is followed by the desired seven-membered
ring formation via Friedel–Crafts acylation.4b,6 As the Friedel–
Crafts acylation was applied successfully in the synthesis of the
azepine framework by our group,5d we expect that the route sug-
gested in Scheme 1 may also allow the synthesis of 4. Com-
pound 6 can be prepared readily from the corresponding ethyl
2-iodobenzoate and acrylates by the Heck reaction.7
We applied these optimized conditions to several sub-
strates, and the desired products were separated in reason-
able yields from 62 to 78% (Table 1). Yields between ethyl
and t-butyl acrylate substrates 5a and 5b did not differ sig-
nificantly. The t-butyl acrylate derivative of 8 was prepared
in 91% yield by using t-butyl acrylate instead of ethyl acry-
late under the same conditions.
Having obtained the amide ester derivatives 5, we applied
practical conditions for the desired intramolecular Friedel–
Crafts acylation. The ethyl esters 5a, 5c, 5e, and 5f underwent
no desired intramolecular Friedel–Crafts acylation. Instead,
the ethyl esters were hydrolyzed to the corresponding carbox-
ylic acids in quantitative yields, and the carboxylic acids or t-
butyl esters were heated in polyphosphoric acid.
Both the carboxylic acid obtained from 5a and butyl ester
5b8 afforded the benzoazepine compounds 4a9 in the modest
yields of 25% to 48%. Derivatives containing methoxy
For a preliminary study of amidation coupling and the aza-
Michael reaction, compound 8, prepared from the correspond-
ing starting materials in 95% yield, was treated with benzyla-
mine under a base catalyst such as triethylamine or K2CO3.
Both products 5a and 9 were obtained in less than 10%
yields. The result suggested that the amidation would provide
compound 9 first, while the following aza-Michael reaction
should yield the desired product 5a (Scheme 2). For this cycli-
zation, the conditions of this step were optimized; using the
Lewis acid MgCl2 (0.5 equiv.) in ethanol under pressure in a
sealed tube at 100ꢀC, afforded 5a in 71% yield. The amount
of ethanol should be as small as possible.
Scheme 1. Synthetic pathway to isoindolobenzo[c]azepine structure.
Scheme 2. Amidation coupling followed by aza-Michael cyclization.
Figure 1. Representative benzo[d]azepine alkaloids.
Bull. Korean Chem. Soc. 2018
© 2018 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communication
ISSN (Print) 0253-2964 | (Online) 1229-5949
BULLETIN OF THE
KOREAN CHEMICAL SOCIETY
Table 1. Products of amidation and aza-Michael cyclization.
gests a new synthetic method for the relatively unexplored
isoindolobenzo[c]azepine alkaloid.
Acknowledgments. This work was supported by Research
Fund of Chungnam National University.
Supporting Information. Additional supporting informa-
tion is available in the online version of this article
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aYields from t-butyl ester.
bYields from carboxylic acid.
Bull. Korean Chem. Soc. 2018
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