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

Sami Dawaigher,Emil Lindbäck,Daniel Strand,Michael Harmata,Anna Cederbalk,Victor Snieckus,Kenneth Wärnmark,Stuart Winikoff,Ramaiah Muthyala

doi:10.24820/ark.5550190.p011.183

Abstract

An efficient synthetic route to the mono-endo-6- and bis-endo,endo-6,12-N,N-diethylcarbamoyl derivatives of Troger’s base (TB), endo-7 and endo-8, is reported. Studies of reaction time, proton source, and additive allowed establishment of optimized conditions for the conversion of exo-7 into the corresponding isomer endo-7. With a longer reaction time, the exo,exo-6,12 bis-carbamoyl derivative exo-8 was converted into the corresponding endo,endo-bis-carbamoyl product endo-8. Single crystal X-ray crystallographic analysis confirmed the structural and stereochemical assignments made on the basis of 1H NMR, mechanistic, and calculational studies. Deuterium quench experiments using LDA, CD3ONa/CD3OD and DCl/CD3OD conditions of both exo-7 and exo-8 afforded exo-7d1 and exo-8d2, respectively (> 95% deuterium incorporation), supporting an enolate mechanism for the isomerization. In contrast, when repeating the experiment with DCl/CD3OD, no deuterium was incorporated, suggesting the traditional ring-opening mechanism involving an iminium ion. (Less)

Highlights

First synthesized in 1887,1 Tröger’s base, 2,8-dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine, (TB, 1, (S,S) in Fig. 1), is a unique V-shaped C2-symmetric molecule with chirality arising from pyramidal nitrogen atoms structurally incapable of undergoing inversion
Examination of the computational mechanism (Scheme 3, Figure 4) indicates that both stereoisomers undergo deprotonation by the diisopropylamide anion, with a thermodynamic driving force of more than 13 kcal/mol and a kinetic barrier less than 20 kcal/mol, suggesting relatively rapid formation of the enolate species, deprotonation is expected to be slower for exo-9 vis-à-vis endo-9, as deprotonation of the former results from removal of an endo hydrogen residing on the concave face of the molecule
We have investigated the synthesis of endo-7 and endo-8 from their corresponding exo isomers (Figure 2)

Summary

Introduction

First synthesized in 1887,1 Tröger’s base, 2,8-dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine, (TB, 1,(S,S) in Fig. 1), is a unique V-shaped C2-symmetric molecule with chirality arising from pyramidal nitrogen atoms structurally incapable of undergoing inversion. At -20 °C, n-BuLi alone (entry 1), with TMEDA (entry 2), or with DIPEA (Hünig’s base) (entry 3) afforded the decarbamoylated product 1, the result of a Haller-Bauer reaction 34 LDA, whether generated In situ (entry 4) or as a commercial stock solution (entry 5), afforded a high ratio of endo-7:exo-7.

Results

Conclusion