A shorter synthesis of symmetrical 2,11-dimethyl-bis-Tröger's bases. A new molecular tweezer

This paper reports a new synthesis of 2,11-dimethyl-bis-Tröger´s bases starting from p - phenylenediamine. The new synthesis is more efficient than those previously described and yields the anti isomer in much higher yield. Isomerization in acidic medium of the anti isomer allowed us to obtain for the first time the syn isomer, a new molecular tweezer


Introduction
As a reasonable approach to explore and amplify the interesting properties of Tröger's base analogues, [1][2][3][4][5][6] and with the aim to use this structural framework unit as building block in the construction of new nanoporous materials and new supramolecular hosts, we have been the first to synthesize bis-Tröger's bases 1 and 2. [7]  In the case of compound 2, an eight-step synthesis starting from p-toluidine, following Wilcox methodology for the synthesis of asymmetrically substituted Tröger's Bases, [8] affords only to the anti isomer in very low yield and with no trace of the most interesting syn isomer. [7]n the case of such symmetrical compounds, it is reasonable to imagine that in the absence of stabilizing π-stacking interactions between identical external phenyl rings, the anti stereoisomer is exclusively formed.These results and conclusions led us to disfavor this synthetic way for obtaining symmetrical dimethyl molecular tweezers.
Subsequently, Král and coworkers described a different and shorter procedure to prepare bis-Tröger's bases from ortho and meta-phenylenediamines [9] in four steps, both methanodiazocine rings being formed in the last one.In all cases only the anti isomer was isolated.Following a similar route starting from p-phenylenediamine, we recently succeeded in the synthesis of the symmetrical dinitro-bis-Bases 3 in only three steps (Scheme 2). [10]By treating pphenylenediamine with two equivalents of 6-nitroisatoic anhydride we obtained the bis-amide 4 that was reduced with borane-SMe 2 complex in anhydrous THF to afford the tetramine 5. Treatment of 5 with aqueous formaldehyde and conc.hydrochloric acid in ethanol at 95 ºC allowed us to obtain an almost equimolecular mixture of both syn/anti steroisomers 3a and 3b.The structure of the dinitro molecular tweezer 3a was unambiguously determined by X-ray crystallography.The formation and isolation of this symmetrical syn isomer, in spite of the hypothesis earlier formulated according to which it would not be favored, have great interest and prompted us to re-evaluated the possibility to synthesize symmetrical syn bis-Tröger's Bases.We thus decided to examine the possibilities to obtain the syn isomer of the dimethyl-bis-Tröger's base 2 possessing a tweezer shape.We report herein a short and convenient synthesis of the bis-Tröger's base 2 together with the isolation of the molecular tweezer 2a.Although these results seem disappointing, we nevertheless decided to realize different attempts to study the possible isomerisation of the anti isomer 2b.In these trials, we chose to vary the experimental conditions (reaction time, temperature, HCl proportion) with the aim to found experimental conditions leading to an efficient synthesis of the syn isomer.After many attempts, we succeeded in preparing the syn isomer 2a by treating 2b with concentrated hydrochloric acid in ethanol at 95 ºC.A 1/1 mixture (ratio determined through 1 H NMR integration) of the two stereoisomers 2a and 2b in an almost quantitative yield was obtained.Both stereoisomers were separated by flash chromatography and identified by 1 H NMR.
HCl, EtOH, 95º The anti stereoisomer 2b was identical to the previously described. [7]The syn stereoisomer 2a was unambiguously identified by 1 H and 13 C NMR at 500 MHz.As reported previously, [8] we can see in Tables 1 and 2 that in the syn isomer the protons of the external aromatic rings are more shielded and that the ∆δ between the exo and the endo protons of the methylene groups H-6( 7) and H-13(18) are larger than in the anti arrangement.

Conclusions
In general, for symmetrical bis-Tröger's bases the approach using p-phenylenediamine as starting material is the best way of access.The isomerization of the anti stereoisomer in acidic medium allows to obtain the most interesting syn stereoisomer in good yield.
ISSN 1424-6376 Page 91 © ARKAT USA, Inc Experimental Section General Procedures.Melting points were determined with a Gallenkamp apparatus and are uncorrected.IR spectra were recorded on a Shimadzu FTIR-8300 spectrophotometer.NMR spectra were recorded with a Bruker AM-200 machine with the exception of those of compounds 2a and 2b which were recorded on a Bruker Avance AV-500 instrument.Chemical shifts are in ppm (internal TMS) and coupling constants in Hz.For TLC Merck silica gel 60 F524 and for chromatographic separations, flash chromatography over silica gel Merck (230-400 mesh) were used.

N,N'-Bis-(2-amino-5-methylbenzoyl)-p-phenylenediamine (7).
A suspension of diamide 6 (500 mg; 1.15 mmol) in ethanol (25 ml) was hydrogenated under 3-4 atm over 10% palladium on charcoal (150 mg) at r.t.during 2 h.The reaction mixture was then filtered and the precipitate, constituted by a mixture of the desired product in the solid state together with palladium on charcoal, was washed with ethanol and the filtrates eliminated.The product was then dissolved in DMSO (10-15 ml) and separated from the palladium on charcoal through filtration.Then water (50 ml) was added to the filtrate and the product isolated by filtration.The filtrate was first washed with dichloromethane and then crystallized in ethanol to afford pure diamide 7 (343 mg).Yield 80%.mp 310-312ºC (dec.).IR (KBr) ν (cm