Diastereoselective synthesis of trans-1 , 2-diamines via sequential opening of cyclohexene oxide and aziridinium ions ( PN-1062 AP )

A synthesis of trans-1,2-diaminocyclohexane derivatives via opening of cyclohexene oxide with secondary amines followed by preparation and opening of the corresponding aziridinium ions in situ by primary and secondary amines is described. Use of chiral α-methylbenzylamine for the opening of aziridinium ions gave a mixure of diastereomers that are readily separated by column chromatography. The C2 symmetric trans-1,2-bis (N-pyrrolidino)cyclohexane was resolved to obtain nonracemic samples that can be readily enriched by co-crystallization with fumaric acid to obtain enantiomerically pure compounds.


Introduction
In recent years, chiral diamines have been widely used as ligands in asymmetric synthesis. 1In particular the salen complexes of chiral diamines have been used in several asymmetric transformations. 2 Also, several biologically active entities are known to contain diamine moieties. 3For example, the C 2 symmetric cyclohexyl diamines 1 and 2 have been reported to give 86% ee in asymmetric dihydroxylation of olefins using OsO 4 . 4The diamine derivatives 3 and 4 are reported to have analgesics activity. 5,6We report here a convenient method of synthesis of the diamine system containing 1,2-cyclohexane moiety via sequential opening of cyclohexene oxide and aziridinium ion derivatives.Use of ammonia and methylamine in the reaction with the aziridinium ion 7a gave the corresponding diamines 8a and 8b in 70% yields (Entries 1 and 2, Table 1).Synthesis of racemic C 2 symmetric amines 8c, 8d and 8e is attained using the same secondary amines for the opening of the epoxide and the aziridinium ion (Entries 3, 4 and 5, Table 1).Reaction of the mesylate 7 using chiral α-methylbenzylamine gave the diastereomeric mixtures of the diamines (8f, 8g) that can be readily separated by column chromatography.4b The yields are of the isolated products, based on the total amount of the starting diamine used.b L (+) DBTA = dibenzoyl-L-tartaric acid, FA = fumaric acid c The resolution was carried out in acetone solvent (30 ml) for 12h.d The resolution was carried out in acetone solvent (15 ml) for 20h.e The reaction was carried out in acetone solvent (5 ml) for 12h.
We have also developed a procedure for the resolution of the C 2 symmetric racemic diamine 8c.Non-racemic samples of 8c with 28%-78% ee are readily obtained by resolution of this diamine with dibenzoyl-L-tartaric acid (Table 2).Enantiomerically pure samples are readily obtained from the nonracemic samples via preparation of the corresponding hydrogen bonded aggregates using fumaric acid (Table 2). 9

Conclusions
The synthetic protocol described here adds to the 1,2-diamines that were previously prepared via opening of azidinium ions prepared in situ, 10 trans-1,2-diamines containing cyclohexane moiety are generally synthesized using the corresponding aziridine derivatives.8b,11 These aziridine derivatives in turn need to be prepared following multi step synthesis.Accordingly, the procedures reported here for the preparation of trans-1,2-diamino cyclohexane moieties via opening of aziridinium ions in situ should make these derivatives more readily accessible.Since, several chiral diamines are useful as ligands in asymmetric synthesis 1,2 and certain derivatives have proven applications in medicinal chemistry, 5 the methods of synthesis of the diamine derivatives described here have good synthetic potential.

Experimental Section
General Procedures.Cyclohexene Oxide, MsCl, pyrrolidine, piperidine, Ammonia solution were purchased from commercial sources.THF solvent was freshly distilled over sodium/benzophenone under nitrogen.Optical rotations were measured in an AUTOPOL-II automatic polarimeter (readability ±0.01).Chromatography was carried out using Acme's silica gel (100-200 mesh) and neutral alumina. 1 H NMR (200 MHz) and 13 C NMR (50 MHz) spectra were recorded on Bruker AC-200 Spectrometer with CDCl 3 as a solvent and TMS as reference (δ =0 ppm).

Typical procedure for preparation of trans-(±)-2-(1-pyrrolidinyl)cyclohexylamine(8a) 12 (procedure A)
Trans-(±)-2-(1-pyrrolidinyl)cyclohexanol (25 mmol) was taken in dry THF (100 ml) and triethylamine (75 mmol) was added and the solution was cooled to 0 o C. To this, methanesulfonyl chloride (30 mmol) was added.The reaction mixture was allowed to stir at 25 o C for 6 h and triethylamine (50 mmol) was added.After stirring at 25 o C for further 2 h, ammonia solution 25% (71 ml) was added and the resulting two-phase reaction mixture was vigorously stirred.After 48 h, the layers were separated and the aqueous layer was extracted with ether.The combined organic extract was washed with 5% aqueous sodium hydrogen carbonate (25 ml), water (25 ml), dried over MgSO 4 and evaporated.Distilled under reduced pressure to obtain the product.