General Protocols for the Synthesis of C₂-Symmetric and Asymmetric 2,8-Disubstituted Analogues of Tröger's Base via Efficient Bromine−Lithium Exchanges of 2,8-Dibromo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine

Abstract

Methods for facile synthesis of symmetric and unsymmetric functionalized analogues of Tröger's base were developed with use of 2,8-dibromo-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (2) as the starting material. C(2)-symmetric 2,8-disubstituted analogues of Tröger's base (4a-f) were synthesized via double bromine-lithium exchange of 2 followed by quench with electrophiles. Desymmetrization via single bromine-lithium exchange of 2, followed by quench with electrophiles, afforded asymmetric analogues of Tröger's base (6a-g). Further reaction of 2-bromo-8-(trimethylsilyl)-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (6b) produced 7a-c via single bromine-lithium exchange and subsequent quench with electrophiles.

Regio‐ and Stereoselective Tether‐Directed Remote Functionalization of C60 with Derivatives of the Tröger Base

“…[7] Thus, diiodo derivative (AE )-3 was prepared from 4-iodoaniline (2) following the protocol of Wärnmark and coworkers (Scheme 1). [8] Subsequent lithium-iodine exchange, followed by the reaction of the dilithiated intermediate with DMF afforded the corresponding dialdehyde, which was reduced (LiAlH 4 ) to diol (AE )-4 and then transformed into bismalonate (AE )-5 by the action of EtO 2 CCH 2 COCl in the presence of DMAP. A modified Bingel reaction [9] of (AE )-5 with C 60 afforded the trans-2 bisadduct (AE )-6 as the major product (27 %).…”

Halogenation of Tröger’s base analogues

“…Mono-halogenated compounds are also available via a stepwise route 37 or desymmetrisation of dihalogenated compounds via lithium-halogen exchange reactions. 26 Bromination of the more electron-rich substrate 2 for 1 h afforded the 1,7-dibromo compound 7 in 60% yield as the major Tröger's base material. Neither starting material nor mono-brominated product was evident by tlc or 1 H NMR analysis of the crude reaction mixture after work-up.…”

“…[17][18][19][20] In the last few years halogenated Tröger's base analogues have been prepared from haloanilines [21][22][23][24] and proven to be extremely valuable in the synthesis of other analogues as the halogens act as "handles" for further functionalisation. [25][26][27][28] As part of a preliminary study aimed at alternate ways of accessing functionalised Tröger's base analogues, a methodology to brominate and chlorinate four Tröger's base compounds, as racemic mixtures, (Figure 1) was investigated. Numerous methods to halogenate aromatic compounds exist, [29][30][31][32][33][34] however, in terms of ease of handling and health issues, N-halosuccinimides are excellent reagents, especially if benzylic halogenation is suppressed.…”

Synthesis and configuration determination of enantiopure 4,10-bis-ortho-substituted Tröger’s base derivatives

“…We hypothesized that the bulkiness of two bis-ortho bromine atoms neighboring N-atoms should be responsible for this. Alternatively, by application of general protocols developed by Wärnmark, 29 double bromine-lithium exchanges of rac-3 were accomplished over 5 minutes using 2.4 equivalent n-butyllithium at -78 °C to afford the corresponding dilithiated intermediate, which was trapped with (-)-menthyl chloroformate to give a 1:1 mixture of two diastereomers (5S,11S)-4 and (5R,11R)-4 in modest yield (Scheme 3). To our delight, the two diastereoisomers (5S,11S)-4 and (5R,11R)-4 were readily separable by silica gel column chromatography.…”