Cyclic nitronic esters from highly diastereoselective cycloaddition of 2-(4-morpholinyl)norbornene to conjugated nitroolefins

The reactions of the morpholino enamine of 2-norbornanone towards a series of cyclic and acyclic conjugated nitroolefins resulted in the formation of the corresponding 1,2-oxazine N-oxides through an exo approach of the electrophiles. The stability of the heterocycles was strongly influenced by the nature of the substituents and in some cases it has been found to be unexpectedly high. Differently from analogous systems, opening of the heterocyclic ring to the corresponding enamine systems was not observed.


Introduction
2][3][4][5][6][7][8][9] In the particular case in which the reacting centres are prochiral, the approach of the two reactants can be either like or unlike 8 and the first step involves the diastereoselective formation of a new carbon-carbon bond in the resulting dipolar intermediate A. The fate of this species does depend on the nature of the reactants and it may lead to different products.The most common is a Michael-type adduct B whose formation derives from abstraction of a proton by the carbanion.Alternatively, the carbanion can collapse onto the iminium carbon atom producing a cyclic compound, which can be either a cyclobutane C or a 1,2-oxazine N-oxide D, through the nitronate form the betaine A, as a result of a formal [2+2] and a [4+2] cycloaddition reaction respectively.In most cases the cycloadducts were not stable and converted eventually to the system B, usually as the less substituted nitroalkylated enamine. 1,2,3he 1,2-oxazine N-oxide systems are of particular interest as this type of heterocycles are highly reactive reagents for 1,3-dipolar cycloadditions 4,8,9 and also as intermediates for the obtainment of γ-nitroketones 1,3,7,8 and γ-diketones 7 which are formed by hydrolysis under different reaction conditions.In this paper we present the synthesis, characterization and reactivity of interesting 1,2-oxazine N-oxides in which the heterocyclic ring is fused to the norbornane ring.

Results and Discussion
The enamine substrate used as a 2π component in this study was 2-(4-morpholinyl)bicyclo [2.2.1]heptene (3).It was prepared by condensation of 2-norbornanone (1) with trimethylsilyl morpholine (2) in the presence of p-toluenesulfonic acid as a catalyst, under gentle heating. 10e 4π components were a series of cyclic and acyclic nitroolefins 4a-k which are listed in Table 1 together with their geometry.The disubstituted nitroolefins were in E configuration with the exception of 4e and 4i which were mixtures of E and Z isomers in the ratio of 7:3 and 9:1 respectively.The reactions between 3 and 4a-k were carried out at low temperatures in order to trap the heterocyclic intermediates.Actually the desired compounds 5 were isolated in all cases with the exception of the reaction of 3 with nitroethylene 4a for which the corresponding nitroketones were obtained directly, although classically anhydrous conditions were used.The 1,2-oxazine Noxide derivatives systems 5 showed in their IR spectra an intense C=N + -O -stretching band in the region 1630-1570 cm -1 , 18 the low frequency range being characteristic of those compounds, such as 5c, 5f, 5i in which a phenyl group was in conjugation with the C=N double bond, while the higher frequency value was observed for 5j and 5k in which the double bond was external to a ring.All heterocycles were pure diastereomers.The only exception was the product derived from α-nitrostilbene, which was a 9:1 mixture of two diastereomers, 5i and 5'i.In all the cases examined the configuration of the heterocyclic ring was always exo with respect to the bicyclic ring, as proved by nOe difference spectroscopy measurements performed on 5g, 5h, 5i and 5'i (Figure 1).Prior to these measurements, proton decoupling experiments and two dimensional spectra allowed the correct assignments to all protons and carbon atoms (Experimental Section).

Figure 1
The configurational assignments for the other 1,2-oxazine N-oxide derivatives were then made by comparing the carbon shifts of the respective bicyclic rings, whose carbon atoms would have been particularly affected by a change in stereochemistry.The values of 13 C shifts of all compounds 5b-k are listed in Table 2, which also includes the value found for 5'i.Although numbering for 5j and 5k is different from that of 5b-i, the carbon atoms occupying the same positions in the rings are listed in the same column for a better understanding.
From a comparison of these data it is evident that there is practically no difference in the absorption values of the bicyclic carbom atoms for all 5b-k.This is particularly true for C-6, C-7 and C-9 which would have been shifted upfield if the configuration were endo and not exo.This observation also holds for 5'i although its steric situation seems more crowded than that present in its isomer.A reason for this feature might be the A 1,2 strain between the two phenyl groups. 19he nOe difference experiments performed on 5'i accounted for a cis relationship of H-4 and H-4a (Figure 1).Also the value of J 44a (9.76 Hz) is in agreement with a quasi eclipsed situation of the protons in question as it is the upfield shift observed for the bridge protons H-9 when compared with those of 5i (1.40, 0.82 ppm vs 2.35, 1.35 ppm) caused by the presence of the phenyl ring at C-4 facing the bridge.Finally, it should be mentioned that the steric encumbrance suffered by the morpholine ring in these systems is such that no rotation and no conformational change is possible, as demonstrated by the broadness of the proton and carbon signals as well as by the fact that nearly each proton and carbon atom of the morpholine ring showed a distinct resonance value.
The thermodynamic stability of the 1,2-oxazine N-oxides 5b-k was much higher than that observed for other analogous systems fused to monocyclic rings.In fact most of them could be stored unaltered in the solid state at -20°C for long periods and some of them even in chloroform solution at room temperature.Furthermore, differently from all the other systems previously studied, compounds 5b-k did not open into the corresponding enamines 7b-k, through the zwitterion intermediates 6b-k, but this latter underwent hydrolysis to the corresponding nitroketones 8a-k, 9a-k.This is probably due to the fact that abstraction of the proton from C-3 by the nitronate oxygen would have been very energy demanding.
When the heterocycles having R 2 other than H were hydrolysed at pH 4-5, a mixture of the corresponding nitroketones 8 and 9 was obtained, in which however the less stable ketone prevailed.Evidently protonation of the nitronate carbon atom in the dipolar intermediate 6 was more or less diastereoselective.Only in a few cases it was possible to assign the correct geometry to the nitromethine carbon atom in the nitroketones (essentially by means of 13 C NMR spectroscopy, see Experimental Section) and hence to determine the preferite side of protonation.This was particularly evident in the case of the hydrolysis of 5k for which the firstly formed mixture of diastereomeric nitroketones 8k (nitromethine proton: W H = 8.0 Hz) and 9k completely equilibrated into 9k having the nitro group equatorially oriented (nitromethine proton: W H = 28.0Hz).
Incidentally, it can be observed that hydrolysis of the 1,2-oxazine N-oxide 5e carried out in acidic medium, albeit moderate, lead to the elimination of the nitro group, via a Nef-type reaction 7 and therefore its opening was accomplished by dissolution in CCl 4 and hydrolysis was then performed by the humidity of the air.
Hydrolyses of the 1,2-oxazine N-oxides 5b,e,h,j,k, carried out at very low pH values, allowed the isolation of the corresponding exo diketones 10b,e,h,j,k and 11b,e,h,j,k through a Nef-type reaction.These latters differed in the configuration of C-1' because of a rapid epimerization of the stereocentre.
The exo-endo equilibration of the diastereomeric mixtures of the nitroketones and those of the diketones could be performed only on heating in refluxing toluene in the presence of ptoluenesulfonic acid as a catalyst.However, although the products were not separated, the exo isomers were always the major components in the mixtures.Equilibration under basic conditions could not be used owing to the presence of the nitro group in 8, 9 and that of two carbonyl groups in 10, 11 which would have lead to condensation products.

Conclusions
The reactivity of the enamine from norbornanone with conjugated nitroolefins showed an exo stereoselectivity, as a consequence of a less steric demand.In the case of nitroethylene a small amount (12%) of the endo nitroketone was detected.(The assignment followed from a comparison with the carbon shifts of 3-methyl-2-norbornanone, 20 see Experimental Section).When the nitroolefins were substituted, in their approach to the the enamine 3 the R 1 and R 2 substituents assumed preferably an exo orientation with respect to the bridge, in accordance with the topological rule by Seebach. 21Therefore this type of attack can be defined exo-exo.The only exception to this rule was just the more hindered nitroolefin, namely 4i, which approached the enamine also in an exo-endo fashion (10%).

Experimental Section
General Procedures.Melting points were determined with a Büchi SHP-20 apparatus and are uncorrected.IR spectra were recorded in CHCl 3 , unless otherwise stated, on a JASCO FT/IR-200 spectrometer. 1 H NMR spectra were run on a Jeol EX-400 (400 M Hz) spectrometer using deuterochloroform as a solvent and tetramethylsilane as internal standard; J value and WH are given in Hz. 13 C NMR spectra were recorded on a Jeol EX-400 (100.4M Hz) instrument.GLC analyses were obtained on a Carlo Erba GC 8000 instrument, the capillary column being OV 1701 25 m x 0.32 mm (carrier gasHe 40KPa, split 1:50, 2 min at 100°C, 3°C/min, 200 °C), Mass spectra were run by the electron impact mode (20 eV and 70 eV) on a VG 7070 spectrometer.TLC were performed on Whatman K6F silica gel plates (eluant: light petroleum/ethyl acetate).Flash chromatography was run on silica gel 230-400 mesh ASTM (Kieselgel 60, Merck) (Eluant: light petroleum/ethyl acetate, gradient from 100/0 to 90:10).Light petroleum refers to the fraction with b.p. 40-70 °C and ether to diethyl ether.

Reactions with the nitroolefins
To a solution of the enamine 3 (1.0 g, 5.6 mmoles) in anhydrous ether was added dropwise a solution of the nitroolefin (5.6 mmoles) in the same solvent, at -45°C, under argon.The reaction mixture was kept at -30°C for 12 h.When a precipitate was formed it was filtered off.