Synthesis of new enantiopure dimethyl-substituted pyridino-18-crown-6 ether type macrocycles containing different substituents at position 4 of the pyridine ring for enantiomeric recognition studies

New enantiomerically pure dimethyl-substituted pyridino-18-crown-6 ether derivatives containing chloro, N -allylamino, N -allylacetamido, N -benzylamino and cyano functional groups at position 4 of the pyridine ring have been synthetized. This paper also reports the transformation of the known enantiopure parent dimethyl-substituted pyridino-18-crown-6 ether to its new N -oxide derivative and the O -methylation of the latter. These ligands are good candidates for enantiomeric recognition studies of protonated primary amines, amino acids and their derivatives.


Introduction
Enantiomeric recognition which is a ubiquitous and vital phenomenon in Nature can also be brought about using relatively simple chiral synthetic host molecules such as crown ethers.Studies using these chiral synthetic mimics not only help to understand better enantiomeric recognition in the living organisms, but it can also lead to the development of new enantioselective sensor and selector molecules with wide applications. 1The first synthetic chiral crown ethers containing the twisted 1,1'-binaphthyl unit were prepared by Cram and coworkers in the 1970's 2 and these optically pure host molecules showed remarkable enantiomeric recognition towards protonated chiral amines and amino acid esters. 3Since the seminal work of Figure 1.Schematics of the reported enantiopure dimethyl-substituted pyridino-18-crown-6 ether parent compound (S,S)-1 and its derivatives (S,S)-2 -(S,S)-9.
Because of their relatively easy synthesis, in all the cases of these optically active dimethylsubstituted pyridino-18-crown-6 ether derivatives, the funtional groups have been attached to the pyridine ring exclusively through an oxygen atom.The manipulation and application of these Oderivatized pyridino ligands, however, are restricted, because nucleophilic attack can take place at position 4 of the pyridine ring as we observed it in the case of the reaction of (S,S)-6 with an alkoxide. 33ery recently we reported the preparation of pyridino-crown ether derivative (S,S)-9 (Figure 1) which is a very useful precursor of an efficient CSP. 32We obtained this precursor from enantiopure dimethyl-substituted pyridono-18-crown-6 ligand (S,S)-10 and N-allylchloroacetamide (11) using K 2 CO 3 as a base in DMF (Scheme 1).(S,S)-9 (S,S)-12 (47%) K 2 CO 3 (DMF) Scheme 1. Preparation of N-allylcarbamoyl-methyleneoxy-pyridino-18-crown-6 ligand (S,S)-9 with formation of side product N-allylaminopyridino-18-crown-6 ether (S,S)-12 and also the degradation of (S,S)-9 to (S,S)-12.
This year we started to prepare larger quantities of ligand (S,S)-9, and when we changed the reaction conditions to improve the yield of this important precursor, we noticed that by increasing the reaction time, and especially the reaction temperature, an appreciable amount of a new product formed which, after isolation and thorough structural analysis, proved to be the unreported N-allylaminopyridino-18-crown-6 ether (S,S)-12.The latter was easily transformed to its N-acetyl derivative (S,S)-13 (see later) which can be a promising precursor for the preparation of a new CSP using the reported procedure. 32he formation of N-allylaminopyridino-18-crown-6 ligand (S,S)-12 promt and motivated us to start the preparation of new enantiopure dimethyl-substituted pyridino-18-crown-6 ether derivatives containing other atoms than oxygen at position 4 of the pyridine ring for the purpose of developing enantioselective sensor and selector molecules with wide applicatioins.
This paper reports only the preparation and characterization of the new derivatives.Their applications as enantioselective sensor and selector molecules will be published in an other paper when the work connected to them is finished.

Results and Discussion
As we mentioned above, when we carried out the reaction of pyridino-crown ether (S,S)-10 with chloroacetamide 11 in the presence of K 2 CO 3 in DMF (Scheme 1.) for prolonged time and especially at elevated temperature, besides the N-allylcarbamoyl-methyleneoxy-pyridino-crown ether (S,S)-9, appreciable amount of N-allylaminopyridino-crown ether (S,S)-12 was also formed.We also treated N-allylcarbamoyl-methyleneoxy-pyridino-crown ether (S,S)-9 with K 2 CO 3 in DMF in the absence of (S,S)-10 and 11, otherwise in the same reaction conditions.The TLC analysis showed that at elevated temperature the degradation of (S,S)-9 to (S,S)-12 was much faster, but completing the reaction took a long time even at elevated temperature and consequently the yield for (S,S)-12 was not very good (Scheme 1).
With the help of Scheme 2. we can rationalize the formation of (S,S)-12 from (S,S)-9.We would like to emphasize in advance that the deprotonation of (S,S)-9 in the given circumstances is not favourable and the equilibrium is shifted backwards to a great extent, but because the last step is irrevesible (formation of gaseous products), the mechanism outlined in Scheme 2 is feasible.
Thus, we suppose that after deprotonation the amide nitrogen attacks the carbon at position 4 of the pyridine ring to give intermediate (S,S)-14I.The latter takes up a proton (either from amide (S,S)-9 or from the hydrogencarbonate anion which forms in the first step, see above) and the intermediate (S,S)-15I so formed breaks down to give formaldehyde, carbon monoxide and (S,S)-12.We note here that adding allylamine to the reaction mixture did not raise the yield of (S,S)-12 which excludes the attack at position 4 of the pyridine ring of (S,S)-9 by allylamine in case of forming some way.
ARKAT USA, Inc.As we were confirmed that (S,S)-12 is a very useful starting material for new CSPs, we wanted to prepare it by another procedure giving a better yield.Lüning and coworkers reported that 4-chloro-2,6-pyridinedimethanol could be transformed to 4-diethylamino-2,6pyridinedimethanol in a good yield by heating the former with an excess of diethylamine at elevated temperature in an autoclave. 36Applying Lüning's method for the preparation of (S,S)-12 first we needed the unreported enantiopure dimethyl-substituted chloropyridino-18-crown-6 ether (S,S)-16 (Scheme 3) which we obtained by treating the known pyridono-crown ether (S,S)-10 33 with an excess of thionyl chloride in boiling chloroform in the presence of catalytic amount of DMF.Heating chloropyridino-crown ether (S,S)-16 with an excess of allylamine in a sealed tube rendered ligand (S,S)-12 in a good yield.The latter was transformed to its N-acetyl derivative (S,S)-13 in a very mild reaction conditions with almost quantitative yield (Scheme 3).
ARKAT USA, Inc. Encouraged by the succesful transformation of chloropyridino-crown ether (S,S)-16 to Nallylaminopyridino ligand (S,S)-12, we also tried the reaction of (S,S)-16 with an excess of benzylamine at elevated temperature.This reaction also went well giving the unreported Nbenzylaminopyridino ligand (S,S)-17 in an acceptable yield (Scheme 4).
Enantiopure N-benzylaminopyridino ligand (S,S)-17 also seems to be a very useful precursor for different pyridino-crown ether derivatives.By removal of the benzyl group from (S,S)-17 by catalytic hydrogenation we can open new routes for further synthetic transformations.
We have long wanted to prepare enantiopure dimethyl-substituted cyanopyridino-18-crown-6 ether (S,S)-18 (Scheme 5), because its cyano group can be transformed to both formyl and carboxyl groups which are excellent functional groups for obtaining new pyridino-crown etherbased sensor and selector molecules.
ARKAT USA, Inc. Studying the reports connected with our plan in the literature we found that Feely and Beavers described the preparation of 4-cyano-2,6-dimethylpyridine starting from 2,6dimethylpyridine by the following steps. 37,6-Dimethylpyridine was treated with 30% aqueous hydrogen peroxide in glacial acetic acid to obtain the relevant N-oxide which was converted to N-methoxy-2,6-dimethylpyridinium methyl sulfate.In the last step the N-methoxypyridinium salt was reacted with an excess of potassium cyanide in water to give 4-cyano-2,6-dimethylpyridine.
For the preparation of cyanopyridino-crown ether (S,S)-18 (Scheme 5) we started from the reported enantiopure dimethyl-substituted parent pyridino-crown ether (S,S)-1 (see also Figure 1.). 14When we treated pyridino-crown ether (S,S)-1 with hydrogen peroxide in acetic acid in the same way as reported for 2,6-dimethylpyridine 37 we obtained only a few percent of N-oxide (S,S)-19, but using m-chloroperbenzoic acid (MCPBA) in CH 2 Cl 2 (Figure 5) we got a good yield for (S,S)-19.Pyridino-crown ether N-oxide (S,S)-19 was reacted with dimethyl sulfate without any solvent to give N-methoxypyridinium salt (S,S)-20 in a good yield.The latter was then transformed to cyanopyridino-crown ether (S,S)-18 using sodium cyanide in a methanol-water mixture with a rather low yield.

Experimental Section
General Procedures.Infrared spectra were recorded on a Zeiss Specord IR 75 spectrometer.Optical rotations were taken on a Perkin-Elmer 241 polarimeter that was calibrated by measuring the optical rotations of both enantiomers of menthol. 1 H (500 MHz) and C (125 MHz) NMR spectra were obtained on a Bruker DRX-500 Avance spectrometer.Mass spectra were recorded on a ZQ 2000 MS instrument (Waters Corp.) using ESI method.Elemental analyses were performed in the Microanalytical Laboratory of the Department of Organic Chemistry, Institute for Chemistry, L. Eötvös University, Budapest, Hungary.Melting points were taken on a Boetius micro-melting point apparatus and were uncorrected.Starting materials were purchased from Aldrich Chemical Company unless otherwise noted.Silica gel 60 F 254 (Merck) and aluminium oxide 60 F 254 neutral type E (Merck) plates were used for TLC.Aluminium oxide (neutral, activated, Brockman I) and silica gel 60 (70-230 mesh, Merck) were used for column chromatography.Ratios of solvents for the eluents are given in volumes (mL/mL).Solvents were dried and purified according to well established 38 methods.Evaporations were carried out under reduced pressure unless otherwise stated.

B. From the degradation of (S,S)-9.
To a solution of N-allylcarbamoyl-methyleneoxy-pyridinocrown ether (S,S)-9 (636 mg, 1.45 mmol) in pure and dry DMF (15 mL) was added finely powdered anhydrous K 2 CO 3 (0.6 g, 4.3 mmol) and the resulting mixture was stirred at rt under Ar for 3 days and at 70ºC for 15 days.After the reaction was completed the mixture was worked up, and the crude product was purified as above (A.)) to give (S,S)-12 (270 mg, 47%) which was identical in every respect to that obtained by the reaction described above under A.). C. From (S,S)-16 and allylamine.Chloropyridino-crown ether (S,S)-16 (200 mg; 0,56 mmol) and allylamine (8 mL, 6.09 g, 107 mmol) were heated in a sealed tube at 120ºC for a week.The excess of allylamine was removed uder reduced pressure, the residue was taken up in CH 2 Cl 2 (30 mL) and the solution was washed with 12.5% aqueous tetramethylammonium hydroxide (4 mL).The aqueous layer was extracted with CH 2 Cl 2 (3X10 mL).The combined organic phase was dried over MgSO 4 , filtered and the solvent evaporated.The crude product was purified as above to give (S,S)-12 (144 mg, 65%) which was identical in every respect to that obtained by the reactions described above under A and B.