An Efficient Synthesis of Bicyclic Amidines by Intramolecular Cyclization

Abstract

Bicyclic amidines and guanidines are organic superbases utilized in various synthetic transformations. Recently, chiral guanidines have been widely explored as non-metal-containing bases in asymmetric synthesis [1] as well as in asymmetric phase-transfer catalysis. [1d, 2] In spite of great success in catalysis with chiral guanidine derivatives, asymmetric reactions with chiral derivatives of bicyclic amidines [3] have not been widely studied, possibly because of the difficulty of synthesizing chiral bicyclic amidines. The nucleophilic character of bicyclic amidines [3c, 4] further broadens their utility as catalysts. Considering the potency of chiral bicyclic amidines as organocatalysts, the development of an efficient protocol for the synthesis of these compounds would greatly contribute toward the progress in this area. [5] For the formation of a bicyclic amidine, the starting material should have two nitrogen-containing functionalities that can assemble intramolecularly to form an amidine core at the ring junction. Previous reports [3, 6] indicate that the intramolecular attack of a free amino group on a lactam in the presence of a strong acid (p-toluenesulfonic acid or TiCl 4 ) [6a] in refluxing xylene, and the intramolecular attack of a Boc-protected amino group (Boc = t-butoxycarbonyl) to a thiolactam under acidic conditions [3a,b, 6c] are reliable (Scheme 1). However, the former method requires harsh reaction conditions, and the latter, too many steps from readily available organic materials although the reaction conditions are mild. We report a concise synthetic procedure for bicyclic amidines starting from readily available tethered azido lactams by means of an intramolecular cyclization (Scheme 1), which provides easy access to various achiral and chiral bicyclic amidines under mild reaction conditions. The direct use of an azido function, instead of an amino group, plays a key role in our reaction design. We also describe mechanistic aspects of the reaction based on an in situ IR study.We focused on the use of an azido group as the nucleophile in the intramolecular cyclization. [7,8] Although

Organische Azide – explodierende Vielfalt bei einer einzigartigen Substanzklasse

“…Eine verwandte Reaktionssequenz zur Synthese von Iminen aus Aziden wurde kürzlich von Shibasaki und Mitarbeitern vorgestellt 524. Sie beobachteten, dass einige Azidoalkyllactame wie 551 unter Staudinger/Aza‐Wittig‐Bedingungen nur langsam oder gar nicht zu den entsprechenden Amidinen reagieren.…”

Tetraazaperopyrenes: A New Class of Multifunctional Chromophores

“…However, very few of them have dealt with the synthesis of its bicyclic counterpart 8. In this sense, lactams appeared as suitable starting materials for an intramolecular attack of an azido group on a lactam function 9. Imidazolines are also synthetic precursors of bicyclic amidines through transition‐metal‐catalyzed microwave‐assisted intramolecularC‐2 alkylation through C–H bond activation 10.…”

Peptide‐Embedded Heterocycles by Mild Single and Multiple Aza‐Wittig Ring Closures

“…[8] On the other hand, the treatment of an azido peptide with phosphanes was reported to lead to fragmentation of the peptide chain, [9] and amide carbonyls tend to display low reactivity. [10] a-Azido acids would be the most general building blocks for the realization of aza-Wittig ring closures on peptides. Accordingly, a-azido derivatives of cysteine (6), serine (7), and threonine (8) were generated on a multigram scale through diazo transfer [11] and the introduction of suitable protecting groups.…”