Synthesis and cis/trans isomerism of N -alkyl-1,3-oxathiolane-2-imines

Reaction of 1-adamantanol with 2-hydroxythiocyanates 2a-d containing imide, ester or ether groups gives N -(1-adamantyl)-1,3-oxathiolane-2-imines 6a-d . Reaction of isoborneol leads to N - bornyl-1,3-oxathiolane-2-imines 6e,f . The barrier of rotation for the imine double bond is measured based on 1 H NMR spectra.

For designation of R and R

Results and Discussion
2-Hydroxythiocyanates react with tertiary alcohols in a mixture of sulfuric and acetic acids, which are to be neutralized in order to separate the products.These acidic conditions limit the substrates of the reaction, since the cations can lead to alkenes, polymerization products and rearrangements.Aryl groups can be involved in the alkylation by the cations.We have found that the compounds 1a-d containing phthalimido, ester and ether groups yield 5-substituted N-(1adamantyl)-1,3-oxathiolane-2-imines 6a-d.The compounds 6a-d can be used to prepare 1,3oxathiolane alcohols and amines, which are interesting for searching biologically active compounds.
Isoborneol is the first secondary alcohol to be successfully used to prepare N-alkyl-1,3oxathiolane-2-imines 6e,f.Alkylation of 2-hydroxythiocyanate by isoborneol seems to be faster than the intramolecular cyclization.The first step of the process is the Ritter reaction employed for thiocyanates. 10But isoborneol can undergo the Wagner-Meerwein rearrangement in the course of the Ritter reaction.For example, the reaction of isoborneol (7) with chloroacetonitrile in sulfuric acid (Scheme 3) gives a 9:1 mixture of 3-exo-(chloroacetylamino)isocamphane ( 8) and 2-exo-(chloroacetylamino)bornane (9)  The reaction of isoborneol with 2-hydroxythiocyanates 2e,f yields the bornyl derivatives 6e,f.The intermolecular reaction of the non-classical isobornyl cation with a thiocyano group seems to be faster than the rearrangement of this cation to the isocamphane structure.The structure of 6e,f was confirmed by 13 C NMR spectra (Table 2).Signals of 6e and isoborneol are very close to each other, whereas the spectrum of the isocamphane derivative 8 is quite different from 6e and isoborneol.Signals of the carbon atoms located far from the polar substituent in 6e and isoborneol have almost the same values.The signals of the isocamphane methylene carbon atoms occur at high field, whereas the methyl signals occur at low field, which can be explained by the position of these atoms and the functional group in the bicyclic cage structure.Table 2. 13 C NMR Signals for bicyclic fragment of 6e, 6f, isoborneol (7) and 3-exo-(chloroacetylamino)isocamphane 11  The bornyl C 2 atom gives two NMR signals, which correspond to the cis/trans isomers.The imino carbon atom also gives two signals.To study the isomerism, 1 H NMR spectra were taken at temperatures 20-95 o C for N-(1-adamantyl)-1,3-oxathiolane-2-imine (6g).The multiplicity of the methylene heterocyclic protons disappears at 75 o C for СH 2 S and at 85 o C for CH 2 O (Fig. 1).The energy characteristics of the isomerization were calculated using the Eyring equation for the rates extracted from the 1 H NMR spectra by the MEXICO line-shape analysis. 12he calculation of linear plot for ln(k/T)-ln(K/h) vs 1000/T gave the following: slope=-7.32±0.15,intercept=-3.92±0.42;where ln(K/h)=23.76024, 12  85.4-91.9kJ/mol for N-isopropyl derivative. 13The lower barrier for N-(1-adamantyl)-1,3oxathiolane-2-imine compared to N-isopropyl-2H-pyran-2-imine can be explained by the conjugation of unshared electrons pairs of the two heteroatoms with the imine bond.

Conclusions
The new route for the preparation of N-alkyl-1,3-oxathiolane-2-imines has been extended to oxiranes containing imide, ester and ether functional groups, and to isobornyl alcohols.The isobornyl cage does not undergo the isomerization during the reaction.Unfortunately, 2adamantanol did not yield any alkylated products because of the intramolecular cyclization of 2hydroxythiocyanate was faster than both the alkylation of the thiocyano group by the 2adamantyl cation and the isomerization of the latter to the 1-adamantyl cation.cis/trans-Isomerism of N-alkyl-1,3-oxathiolane-2-imines has been confirmed by 13 C NMR data and the energy barrier of the rotation around the C=N bond has been calculated from the temperature dependence of 1 H NMR spectra.

Experimental Section
General Procedures.Melting points were determined on a hot-stage apparatus and are uncorrected.IR spectra were recorded on a Shimadzu FTIR-8500S spectrometer, mass spectra were recorded using DEP mode on Finnigan DSQ GC-MS with an ionization potential of 70 ev, 1 H and 13 C NMR spectra were recorded in CDCl 3 with TMS as the internal standard for 1 H (90 MHz) and 13 C (22 MHz). 1 H NMR spectra at temperatures 20-100 o C were recorded in DMSO-d 6 for 1 H (300 MHz).

General procedure for the preparation of 6a-d,g
A solution of ammonium thiocyanate (5 g, 0.065 mol) and oxirane 1a-d (0.08 mol) in glacial acetic acid (15 ml, 0.25 mol) was stirred for 1-2 h.The acetic acid solution was added dropwise to a solution of 1-adamantanol (8 g, 0.053 mol) in sulfuric acid (30 ml, d 1.84) at 5-10 o C. The reaction mixture was poured on ice followed by extraction with chloroform and neutralization with sodium carbonate.The crude product was extracted with methylene chloride, filtered through a silica gel and the solvent was distilled off.

General procedure for the preparation of 6e-f
A solution of ammonium thiocyanate (5 g, 0.065 mol), oxirane 1e-f (0.08 mol) and isoborneol (8 g, 0.053 mol) in glacial acetic acid (15 ml, 0.25 mol) was stirred for 1-2 h.The acetic acid solution was added dropwise to sulfuric acid (30 ml, d 1.84) at 5-10 oC.The following work up was the same as for 6a-d.