An unexpected ring formation in morphine chemistry

Reaction of (7 R )- N -benzyl- N -nor-7-bromoneopinone dimethyl acetal ( 2 ) with primary or secondary amines (RNH2, R1R2NH) resulted in 9-amino-substituted hasubanan derivatives; in particular, modification of the 9-(2-hydroxyethyl)amino derivative in subsequent steps gave products 8 with a 9-(oxazolidin-2'-one-3'-yl) substituent. 1 H and 13 C NMR spectra did not provide definitive evidence for the supposed structure and reaction mechanism, but X-ray analyses of compounds 8a and 8d confirmed both structures.


Introduction
It is known that the position of basic nitrogen in the morphine scaffold as well as the type of its substituents are of great importance with regard to the interaction with the anionic site of the receptor.The goal of our approach was to introduce a second basic group in the vicinity to the nitrogen attached to C-9.The subsequent step should turn the original nitrogen atom into a nonbasic group, incapable of interaction with the anionic site of the receptor.In this way the scaffold nitrogen would be changed to inefficiency whereas the newly inserted one could be capable of pharmacologic interactions.
Two more points of consideration should be mentioned: 1.A second nitrogen offers the advantage to insert an intramolecular bridge.2. The synthesis of dimers by inserting suitable bivalent reagents should be possible; such compounds are known to possess higher antinociceptive potency and receptor selectivity by entropic reasons. 1

Scheme 1
We started as follows (Scheme 1): Reaction of the known 14,17-cyclonorcodeinone dimethyl acetal 1 2 with benzyl bromide yielded quantitatively the neopinone derivative 2. 3 Generally, hydrolysis, methanolysis, acetolysis, i.e. nucleophilic substitution of 7-bromoneopinone or 14bromocodeinone acetal derivatives are assumed to occur via an ionic intermediate (a quaternary aziridinium ion derived from 1), which results in a mixture of 7-, 14-and 9-substituted derivatives. 4Therefore, the straightforward reaction with primary and secondary amines furnishing single, defined products was a surprise at first sight.Inspection of the NMR spectra of the product eliminated structure 5, but it was not possible to discriminate unambiguously between amine substitution at C-9 (as in 3) or C-14 (as in 4) by any routine analytical method.Only the 1 H NMR spectrum of derivative 3d, obtained later, gave evidence in support of the proposed structure based on the paramagnetic shift of the H-9 signal as a consequence of carbamate formation.We expected that synthetic steps to be carried out at a later stage and aiming at cyclisation by bridging both nitrogen atoms would support this indication, but at last the X-ray analyses of 8a and 8d confirmed the substitution at C-9. isolation of the resulting intermediate and was expected to facilitate the desired intramolecular reaction by increasing the electrophilicity of the terminal methylene group (Scheme 2).Surprisingly, we did not obtain the quaternary ammonium salt 6 or 7, but rather a product in high yield and with concomitant loss of one benzyl group.Later this product was identified as the oxazolidinone derivative 8a (vide infra).At first, we were not aware of this and believed that a diazine moiety had been formed, and keeping in mind the loss of one benzyl group we set out to distinguish between a product structure derived from either 6 or 7.
It is noteworthy to mention that the decisive condition for this unique reaction leading to 8a is the presence of dimethylaminopyridine (DMAP) in the tosylation step which triggered the entire reaction sequence: nucleophilic attack of DMAP at the O-benzyl methylene group induced CH2-O-bond cleavage and ring closure by the carboxyl oxygen at the tosyloxymethylene group with displacement of the tosylate anion.The benzyl group of the Z-group was consumed by DMAP affording the N-benzyl-4-(dimethyl-amino)pyridinium ion, which was precipitated as the perchlorate salt and analyzed after crystallisation.Without the assistance of DMAP no reaction was detectable.
Compound 8a was debenzylated to 8b by hydrogenation over Pd/C-catalyst in acetic acid.Finally, the structure elucidation of 8d and 8a by X-ray analyses ensured that the oxazolidine derivative had in fact been formed.This result eliminates structure 9 and that of its conceivable precursor 4e.

Crystal structure discussion
Eventually, the structure of compounds 8a and 8d was proven by X-ray analysis (Figures 1 and  2).

Experimental Section
General Procedures.Melting points: Kofler hot stage microscope; column chromatography was performed on silica gel (Kieselgel 60, 70-230 mesh; Merck).IR spectra were recorded on a Perkin Elmer Spectrum 1000 instrument; NMR spectra were recorded on a Varian Unity Plus 300 spectrometer; mass spectra were measured on a Shimadzu QP-5000 mass spectrometer (EI, 70eV).Elemental analyses were performed by the Laboratory of Microanalysis, Institute for Physical Chemistry of the University of Vienna.Energy computations were accomplished using the CS Chem 3D Pro ® program (MM2 force field), Cambridge, MA.

Figure 2
Figure 2 Perspective view of compound 8d with atom labeling scheme.