Derivatization of 1-phenyl substituted 4-amino-2-benzazepin-3-ones: evaluation of Pd-catalyzed coupling reactions

Abstract

Several Pd-catalyzed reactions were explored to further functionalize the bromo-substituted 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one scaffold (Aba). We report in this paper suitable reaction conditions for Suzuki, Buchwald–Hartwig, and Heck reactions. The substitution pattern of the starting aminobenzazepinone turned out to be crucial for the success of these transition metal-catalyzed reactions, which often required modifications of standard literature procedures. The Pd-catalyzed methods provide access to novel substitution patterns of the Aba scaffold.

Introduction

The 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) skeleton 1 is present in several bioactive compounds (Fig. 1).1, 2, 3, 4, 5 This template is the basic unit in ACE-,¹ NEP-,² and farnesyl transferase inhibitors,³ fibrinogen receptor antagonists,⁴ and analgesics.⁵ Synthetic methods, that allow the efficient introduction of a variety of substituents at different positions, are therefore of high value from a medicinal chemistry point of view.

Our research group has reported several methods to prepare disubstituted,6, 7, 8 trisubstituted,9, 10 and tetrasubstituted¹¹ 4-amino-2-benzazepin-3-ones with a wide range of substituents, but until now we never explored the possibilities to further derivatize the scaffold. Since drug development is often based on further ‘functionalization’ of an already existing lead compound, a convergent method for modifying a common intermediate would increase the efficiency of the synthesis. An interesting strategy to introduce new vinyl-, aryl-, arylamino- or alkylamino-type substituents, that would serve as eventual pharmacophoric groups, is to use Pd chemistry. In this way new C–C and C–N bonds should be easily formed in the late stage of the synthesis route of the target compounds.

The substrates for the evaluation of the Pd-catalyzed methods were the phthaloyl-protected bromo-substituted Aba analogs 2 and 3 obtained through two different, earlier reported, N-acyliminium ion based cyclizations A and B, depicted in Scheme 1.¹¹ Method A allows the simultaneous introduction of a substituent at positions 1 (R¹ in 1) and 2 (R² in 1), although there were limitations for the choice of the 2-substituent, caused by steric hindrance. No cyclohexyl group could, for example, be introduced as an R² substituent. The method yields a 1:1 mixture of stereoisomers. Method B, a procedure based on Katritzky's benzotriazole chemistry,¹² allowed the introduction of different 1-substituents and yields selectively the cis-stereoisomer. Only R²=H was however allowed.¹¹ Despite the lower reactivity of the aromatic ring in 6 (due to the bromine atom) for ring closure of type B (Scheme 1), we were able to prepare compound 3. This 8-bromo-substituted analog is unavailable through method A as reported earlier.¹¹ The aryl bromide moiety in scaffolds 2 and 3 allows to further elaborate functionalization at these positions via Pd-catalyzed reactions. For this purpose, we explored Buchwald–Hartwig aminations, Heck alkenylations, and Suzuki arylation reactions on 2 and 3.