Abstract
Rapid access to allylic trichloroacetimidates bearing a 2-allylaminoaryl group from readily available 2-iodoanilines combined with a one-pot multibond forming process has allowed the efficient synthesis of a series of 5-amino-2,5-dihydro-1H-benzo[b]azepines. The potential of these compounds as synthetic building blocks was demonstrated by the preparation of a late-stage intermediate of the hyponatremia agent, mozavaptan.
Highlights
1H-Benzo[b]azepines are an important class of sevenmembered heterocyclic compound found as a key structural element in a wide variety of pharmaceutically active substances.[1,2] Within this class, 5-amino-2,3,4,5-tetrahydro1H-benzo[b]azepines are of particular significance and include compounds such as mozavaptan (1), a nonpeptide vasopressin V2-receptor antagonist used for the treatment of hyponatremia,[3] and 3,5-bis(trifluoromethyl)benzyl protected 2,3,4,5-tetrahydro-1H-benzo[b]azepine 2, developed for the treatment of dyslipidemia (Figure 1).[4]
Due to the pharmacological importance of 5-amino-2,3,4,5tetrahydro-1H-benzo[b]azepines, a number of methods have been developed for their synthesis.2,3c,6 Traditionally, a Dieckmann condensation has been used to prepare 1Hbenzo[b]azepin-5-ones, followed by introduction of the amino substituent by reductive amination of the ketone (Scheme 1a).2c More recently, the azepine ring system in these compounds has been prepared using methods such as the Beckmann rearrangement,6b the Mitsunobu reaction,6a reductive ring opening of aza-bridged azepines,6e and ring closing metathesis (RCM) (Scheme 1b).6d,7 With the aim of developing new methods for the preparation of highly functional polycyclic compounds, we have demonstrated that benzannulated alkene derived allylic alcohols could be used in one-pot multireaction processes for the efficient synthesis of amino-substituted indenes, dihydronaphthalenes, and 1-benzoxepines.[8]
We report a short and general synthesis of allylic trichloroacetimidates bearing a 2-allylaminoaryl group from readily available 2-iodoanilines and demonstrate the application of these compounds in a one-pot multibond forming process for the efficient synthesis of 5-amino-2,5-dihydro-1H-benzo[b]azepines (Scheme 1c)
Summary
1H-Benzo[b]azepines are an important class of sevenmembered heterocyclic compound found as a key structural element in a wide variety of pharmaceutically active substances.[1,2] Within this class, 5-amino-2,3,4,5-tetrahydro1H-benzo[b]azepines are of particular significance and include compounds such as mozavaptan (1), a nonpeptide vasopressin V2-receptor antagonist used for the treatment of hyponatremia (low blood sodium levels),[3] and 3,5-bis(trifluoromethyl)benzyl protected 2,3,4,5-tetrahydro-1H-benzo[b]azepine 2, developed for the treatment of dyslipidemia (Figure 1).[4]. Synthetic Approaches for the Preparation of 5Amino-Substituted 1H-Benzo[b]azepines. Amino-2,3,4,5-tetrahydro-1H-benzo[b]azepines has led recently to a detailed analysis of their conformational bias and a greater understanding of their physicochemical properties.[5]. Due to the pharmacological importance of 5-amino-2,3,4,5tetrahydro-1H-benzo[b]azepines, a number of methods have been developed for their synthesis.2,3c,6 Traditionally, a Dieckmann condensation has been used to prepare 1Hbenzo[b]azepin-5-ones, followed by introduction of the amino substituent by reductive amination of the ketone (Scheme 1a).2c More recently, the azepine ring system in these compounds has been prepared using methods such as the Beckmann rearrangement,6b the Mitsunobu reaction,6a reductive ring opening of aza-bridged azepines,6e and ring closing metathesis (RCM) (Scheme 1b).6d,7 With the aim of developing new methods for the preparation of highly functional polycyclic compounds, we have demonstrated that benzannulated alkene derived allylic alcohols could be used in one-pot multireaction processes for the efficient synthesis of amino-substituted indenes, dihydronaphthalenes, and 1-benzoxepines.[8] We report a short and general synthesis of allylic trichloroacetimidates bearing a 2-allylaminoaryl group from readily available 2-iodoanilines and demonstrate the application of these compounds in a one-pot multibond forming process for the efficient synthesis of 5-amino-2,5-dihydro-1H-benzo[b]azepines (Scheme 1c)
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