Synthesis and Characterisation of Macrocyclic Diamino Chiral Crown Ethers

A benign and efficient synthesis of chiral macrocyclic ‘aza-crown’ ethers of varying ring size is reported. The synthesis involves a Schiff base condensation of ether linked dialdehydes of varying chain length and (1R,2R)-(–)-1,2-diaminocyclohexane under mild conditions to yield the macrocycles, which are subsequently reduced to yield the diamino analogues.


Introduction
In 1998 Kaupp reported the facile solvent-free condensation of aryl amines and benzaldehyde derivatives to produce azo-methines [1]. This is an advantageous and facile route as it negates the generation of excessive waste whilst proceeding more efficiently than corresponding solution phase methodologies. This approach has subsequently been extended to corresponding amine derivatives such as the tetrahydroquinazolines [2]. More recently, we have adopted an analogous, simple procedure that allows for the efficient generation of some macrocycles derived from the reduction of Schiff bases formed using enantiomerically pure diamine precursors. We now report the synthesis of a number of novel, chiral, macrocycles not previously described or tested for this application.

Results and Discussion
Dialdehydes 1 are condensed with enantiomerically pure trans-cyclohexanediamine to form the Schiff base 2 followed by reduction with sodium borohydride to afford the aza crown analogues 3 (Scheme 1). The synthesis of dialdehyde ether linkers 1 has been reported previously [3,4] and involves the conversion of glycols to di-bromo ethers followed by a Williamson etherification of salicylaldehyde to yield the desired precursors. We were able, through some minor modifications and application of novel microwave technology, to improve upon the overall efficiency of this preliminary process.
Compounds 2a and 2b could be synthesised in the absence of solvent by simply grinding the reactants together at room temperature, however, this neat approach was not as effective for 2c and 2d, as dialdehydes 1c and 1d are oils at room temperature. In these instances Schiff base formation was achieved in ethanolic solutions, the product separating as an oil. Reaction times and yields for both steps are included in Table 1.
Scheme 1 In most cases the reduced macrocyclic products 3 were isolated as oils. Subsequent purification involved the precipitation of hydrochloride salts by reaction with excess hydrochloride in ether. The 1 H-and 13 C-NMR spectra of the respective Schiff bases 2 and diamino products 3 were consistent with the assigned structures in all cases. There was no spectroscopic evidence for the presence of any imine protons once the reduction had been performed. This reduction step needed to be conducted under relatively forcing conditions, utilising a vast excess of reducing agent and at elevated temperature, as the macrocycles 2 were poorly soluble in ethanol.

Tab
All of the macrocycles synthesised are optically active. The absence of peaks at higher m/z values than that expected for the corresponding parent ion (LH + ) in the electrospray ionisation mass spectra attest to exclusive formation of 1:1 condensation products. The Schiff base infrared spectra confirms the presence of the imine C=N stretch with a sharp band in the region 1630-1640 cm -1 . These bands are absent in the reduced product. The HCl salts are all hygroscopic, and in the case of 3a and 3d, there was microanalytical as well as spectral evidence for the formation of 1:1 hydrates. In addition, the salts appear to complex common solvents, which are subsequently difficult to remove, even under vacuum at elevated temperature. The presence of solvates, was inferred from the existence of corresponding signals in 1 H-NMR and infrared spectra. Repeated attempts to crystallise the macrocycles resulted in oils or glasses, though the HCl salts are afforded as finely divided white solids.

Conclusions
We have developed a facile and high yielding route for the formation of a novel class of chiral diamino macrocyclic compounds incorporating ether chains.

Acknowledgements
This project was supported by the Centre for Green Chemistry and we thank Arran Chemical Company Ltd. for a gift of (1R,2R)-(-)-1,2-diaminocyclohexane.

General
All reagents were of 98 % purity or greater and used as obtained from the supplier unless noted otherwise. Grinding experiments were performed with porcelain mortar and pestles, which were rinsed with acetone and dried prior to use. All melting points were determined on an Electrochemical digital melting point apparatus. 1 H-NMR and 13 C-NMR spectra were recorded on either a Varian Mercury 300 MHz or Bruker DRX400MHz. spectrometers. Chemical shifts were referenced relative to CDCl 3 or CD 3 OD. Electrospray Mass Spectroscopy (ESI) was carried out on a Micromass Platform II API QMS Electrospray Mass Spectrometer with cone voltage at 35 V, using acetone as the mobile phase. Analyses were conducted both in positive (ESI + ) and negative (ESI -) mode. Infrared spectroscopy was carried out on a Perkin Elmer FTIR-1600 with samples were prepared as KBr discs. Specific rotations were measured on a Hewlett Packard Polar 3005 polarimeter. Microanalyses were conducted on the HCl salts of the reduced macrocycles.

General Procedure for the Synthesis of Diamino Macrocycles
An equimolar quantity of the relevant dialdehyde 1 together with (1R,2R)-(-)-1,2-diaminocyclohexane was ground using a mortar and pestle at room temperature for approximately 5 minutes. The resultant powder was washed with cold ethanol; in the case of 2c and 2d the corresponding dialdehyde precursors are oils at room temperature and, consequently, the condensation was carried out in absolute ethanol at room temperature. After 20-30 min the oily products began to separate from solution; after 4.5 h the supernatant was decanted yielding the desired Schiff base. The larger macrocyclic products are all pale yellow oils, (only 2a is a solid), and were purified by washing with hot ethanol. The respective Schiff bases were combined with 10 mol equiv. of NaBH 4 in absolute ethanol. The reaction mixture was heated under reflux for 4-5 h, cooled and quenched with distilled water. Solvent was removed in vacuo and the product extracted into dichloromethane. The organic layer was washed twice with brine, dried with MgSO 4 and concentrated to afford the products as pale yellow oils. Spectroscopic data is given for the free base. The dihydrochloride salts were obtained by dissolving the oils in dichloromethane and adding an excess HCl in ether. White or pale yellow gummy solids formed instantly which were triturated and washed with hexane and filtered off.