Facile and simple synthesis of N -alkyl and N -aryl 2-benzazepines by nucleophilic heteroannulation

Article abstract of DOI:10.1080/00397911.2014.928327

An efficient and practical synthesis of N-alkyl and N-aryl 2-benzazepine has been developed. The key steps involved in the synthesis were palladium-mediated Heck reaction followed by aza heterocyclic ring construction by nucleophilic heteroannulation. This four-step sequence synthetic protocol gave moderate to good yields for a wide range of substrates. Subsequently, functionalization of the synthesized compound was carried out under Heck and Suzuki reaction conditions.

Full text of DOI:10.1080/00397911.2014.928327

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A Facile and Simple Synthesis of N-Alkyl and N-Aryl 2-
Benzazepines by Nucleophilic Heteroannulation
A. K. Srinivasan a , K. Rajashekar a , Shyamapada Banerjee a & U. K. Syam Kumar a
a Custom Pharmaceutical Services, Dr Reddy's Laboratories Limited, Bollaram Road,
Miyapur , Hyderabad , India
Accepted author version posted online: 09 Jun 2014.
To cite this article: A. K. Srinivasan , K. Rajashekar , Shyamapada Banerjee & U. K. Syam Kumar (2014): A Facile and Simple
Synthesis of N-Alkyl and N-Aryl 2-Benzazepines by Nucleophilic Heteroannulation, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2014.928327
To link to this article: http://dx.doi.org/10.1080/00397911.2014.928327
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A Facile and simple synthesis of N-Alkyl and N-Aryl 2-Benzazepines by nucleophilic
heteroannulation
A. K. Srinivasan1, K. Rajashekar1, Shyamapada Banerjee1, U. K. Syam Kumar1
1Custom Pharmaceutical Services, Dr Reddy’s Laboratories Limited, Bollaram Road,
Miyapur, Hyderabad, India
Corresponding Email: srinivasanak@drreddys.com
Abstract
An efficient and practical synthesis of N-alkyl and N-aryl 2-benzazepine has been
developed. The key steps involved in the synthesis were palladium mediated Heck
reaction followed by aza heterocyclic ring construction by nucleophilic heteroannulation.
This four step sequence synthetic protocol gave moderate to good yield for a wide range
of substrates. Subsequently, functionalization of the synthesized compound was carried
out under Heck and Suzuki reaction conditions.
KEYWORDS: 2-benzazepine, Heck reaction, nucleophilic heteroannulation, Suzuki
reaction.
INTRODUCTION
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The 2-benzazepine is not only a unique aromatic fused aza-heterocyclic structure but also
is a core component of a number of pharmacologically important compounds [1].
Benzazepine derivatives exhibit a variety of biological activities such as analgesic,
antiarrhythmic, anticonvulsant, hypertensive activities [2] and peptide mimic of RGD
motif [3]. Further; it would be useful antagonists of muscarinic (M3) receptors. In
addition, these compounds are helpful for treatment of mental disorders and hypoxia [4].
Recently benzazepine derivatives are reported as a potential drug candidate to prevent
cell-cell adhesion [5]. Benzazepine skeleton is a main part for many naturally available
alkaloids of the amaryllidaceae group such as cripowellin A lycoramine, narwedine etc.,
and equally benzazepine core structure found in various active pharmaceuticals
ingredients such as mirtazapine, galanthamine[6] etc. Due to the diverse pharmacological
properties, benzazepine heterocycles have drawn our attention to explore the synthesis of
novel 2-benzazepines via an efficient methodology.
There are several known synthetic reports available in the literature for the synthesis of 2-
benzazepine, such as Pictet-Spengler cyclization [7], Bischler-Napieralski protocol [8],
Beckmann or Schmidt rearrangements of 3, 4-dihydro-1(2H)-naphthalenone[9], using
ring-closing metathesis methodology [10], functionalized benzyl amine or benzyl chlorides
cyclization [11] and using one-pot transformation of the Baylis–Hillman adducts via the
simultaneous Ritter and Houben–Hoesch reactions [12]. Other striking synthesis are
TMSOTf promoted Friedel–Crafts reaction of vinyloxirane [13], Rhodium-Catalyzed
hydroaminomethylation [14], construction of 2-benzazepine by TiCl4-Mediated Tandem
Mannich Reaction [15] and synthesized from substituted cinnamylamide via an
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intramolecular Friedel−Crafts reaction [16]. Though synthesis of 2-benzazepine was
widely reported, significant efforts have been made to develop a simple and efficient
synthesis of 2-benzazepine.
Palladium-mediated coupling reactions are very much interested due to their versatility
and high functional group tolerance. Among all palladium-mediated coupling reactions,
Heck reaction is more attractive due to their clean reaction profile and less formation of
side product towards the formation of C–C bond of aryl halides or vinyl halide with
activated olefins [17]. The Heck cross coupling was employed for the synthesis of the key
intermediate 3-(2-(hydroxymethyl)phenyl)propan-1-ol (4) which is the structural
requirement for the synthesis of benzazepine frame work. It could be easily converted in
to 2-benzazepine derivatives by nucleophilic heteroanulation reaction. In our present
work, we wish to now report preparation of N-alkyl and N-aryl 2-benzazepines and also
like to report further functionalization of 2-benzazepine for generating novel and
structurally diversified benzazepines derivatives.
RESULTS & DISCUSSION
Our approach started for the synthesis of 2-benzazepine from commercially accessible
methyl 2-bromobenzolate (1) (Scheme 1). It was treated with methyl acrylate using Heck
reaction protocol which afforded E-arylalkene diester 2[18]. To find the best experimental
conditions for the Heck coupling reaction we have carried out the reaction with different
palladium catalyst in various solvents / bases. The details are listed in Table 1. It was
found that the best result was obtained when the reaction was carried out with 5 mol%
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