On the Synthesis of Asymmetric and Dissymmetric Amino Analogues of ­Tröger’s Base

Abstract

Monoamino and diamino analogues of Tröger's base have been synthesized by palladium-catalyzed aminations of the corresponding dihalo analogues using low catalyst loadings. Depending on the nature of the dihalo analogue (Br or I), catalyst loading and the scale of the reaction, monoamino-monohalo and/or diamino analogues of Tröger's base were obtained. Tröger's base, 2,8-dimethyl-6H, 12H-5,11-methanodibenzo[b,f][1,5]diazocine (1; Figure 1), has drawn the attention of chemists over the years due to the presence of a concave V-shaped aromatic surface and because of its inherent dissymmetry arising from the presence of stereogenic nitrogen atoms in a rigid frame. 1 These properties have rendered the Tröger's base framework an attractive building block for applications in the field of molecular recognition and in supramolecular chemistry, but analogues have also been used as enzyme inhibitors, ligands in asymmetric synthesis, as torsional balances to determine weak intermolecular forces and as functionalized fullerene analogues. 2 To the class of Tröger's base analogues has recently been added metallomacrocycles and a-amino acids. 3 (1) The synthesis of analogues of Tröger's base has been hampered by the lack of a general methodology with which to functionalize the Tröger's base core. In particular, it had been argued that the Tröger's base condensation reaction, the condensation between anilines and formaldehyde under acidic conditions, was hampered by the presence of electron-withdrawing substituents in the corresponding anilines. 4 A few years ago we discovered that halogenated analogues of Tröger's base could be synthesized using trifluoroacetic acid (TFA) and paraformaldehyde under controlled reaction conditions. 5 The reaction has been optimized for larger scale preparation, initially by us 6 and later by Sergeyev and Diederich 7 as well as by Bew. 3b The advent of dihalo-substituted analogues of Tröger's base has allowed further functionalization of the Tröger's base core by two different methodologies. One methodology involves either a single or double halogen-lithium exchange reaction followed by quenching with various electrophiles, producing asymmetric and dissymmetric Tröger's base analogues. 8,9 The second methodology uses the difunctionalization of dihalo analogues of Tröger's base by cross-coupling strategies and was first introduced by us on this system 5a and further developed by us and others. Such approaches include: Corriu-Kumada cross-coupling, 5a the Sonogashira reaction, 10a,b Suzuki, 10b-d Stille, 10c Negishi 10c cross-couplings, and palladium-catalyzed cyanations 10d and coppercatalyzed amidations. 10d Figure 1 Tröger's baseIn a project devoted to the synthesis and study of fused analogues of Tröger's bases as cleft compounds, 11 we became interested in the synthesis of 2-amino-8-bromo analogues of Tröger's base. Thus, following our single halogen-lithium exchange desymmetrization protocol mentioned above, the 2,8-dibromo analogues of Tröger's base 2 11b (0.9 mmol) and 3 5a,6 (3.2 mmol), were...

Mono-endo-6-N,N-diethylcarbamoyl and bis-endo,endo-6,12-N,N-diethylcarbamoyl derivatives of Tröger’s base. Synthesis and exo-endo isomerization study

“…18,19 Recent reviews detail the numerous possible applications of this important molecule and its congeners. 20 Due to the versatility of 1 and its derivatives, many research groups 24 including ours, [25][26][27][28][29][30] have developed procedures to modify 1 to prepare new derivatives and analogues. Having functional groups pointing towards the inside of the chiral pocket of 1 might allow the installation of new binding sites on the concave face of TB.…”