STEREOSELECTIVITY IN THE REACTIONS OF NITROSOPIPERIDINE CARBANIONS, STERIC VERSUS STEREOELECTRONIC CONTROL

ion may be the result of several factors, evidence was presented (6) that the enhanced stability of the carbanion due to nitrosation of ZThe preliminary account (6) of this work set only a lower limit to the selectivity. The more accurate measurements quoted above will be published shortly (8). 2474 CAN. J. CHEM. VOL. 53, 1975 the nitrogen atom results from a contribution of structure c to the hybrid anion of 1 (see a, b, c). When the anion of 1 was formed by treatment with lithium diisopropylamide (LDA) in THF at -78", subsequent methylation and carboxylation produced syn-axial substitution only (7). In view of the synthetic potential of these anions, it seemed im~ortant to broaden our studies of their ~tereoseiectivit~. We now wish to report the stereochemical course of several reactions of Nnitroso-4-phenylpiperidine (2). This molecule, being conformationally homogeneous, should provide useful information on the stereoselectivity of these anion reactions. Reactions of 2 The anion of 2 was generated by reaction with LDA in THF at -78" for 4-30 min (see Experimental). Subsequent addition of the electrophile followed by a reaction time of up to 1 h, then work-up, gave good yields of a-substituted products. For example, carboxylation, methylation and condensation with benzophenone proceeded in yields of 76, 79, and 72%, respectively. The important feature of all three reactions is the exclusive formation of trans products, 3, 4, and 5 (axial substitution only). We can estimate that more than 1% of cis product would have been detected by n.m.r. or the careful t.1.c. search. Thus, these three reactions of 2 are highly stereo~elective.~ We next examined the reactions of N-nitrosor-2-methyl-t-4-phenylpiperidine (4). Methylation by the standard procedure gave the dimethyl derivative (6) in 62% yield and carboxylation of 4 gave 7 in 33% yield. Again, in both reactions, substitution gave only axial product. Owing to the greater complexity in the methyl region of the p.m.r. spectrum of 6, as much as 2% of 8, the product of equatorial attack, might be undetected. The fact that no trace of 8 could be found by t.1.c. indicates that < 1% is a more probable upper limit. Equilibration of 6 To further our understanding of the stereo3Since methylation of 1 was shown to be exclusively syn, we have not attempted to verify the syn selectivity in the reactions of 2. We have observed a predominance of syn isomer in the methylation of 2 and assume the small amount of anti results from rotation about the N-N bond during work-up. The half-life for this process, as measured by equilibration of the dominant syn isomer 4, is 2 h. by p.m.r L and c.m.r 0 FIG. 2. The conformational properties of N-nitroso2-methylpiperidine. selective methylation, information on product stabilities was sought. A sample of 6 was subjected to isomerization conditions (potassium tbutoxide in DMSO at 90" for 24 h). At the end of this time, the proportion of 8 to 6 was 74: 26. Pure 8 was then isolated and subjected to the same isomerization conditions. A trans to cis ratio of 75: 25 was produced. Some darkening of the solution occurred during both equilibrations, indicative perhaps of decomposition. However, 63% of material was recovered after isomerization. We can conclude that the observed proportion of trans to cis is quite close to the equilibrium value. In the accompanying paper (9), both lH and 13C spectral evidence established the chair conformation and the orientation for the methyl groups of the three nitrosamines 4, 6, 8. Using these 13C data, it was possible to determine the conformational properties of N-nitroso-2-methylpiperidine, with a degree of certainty which previous work in the literature lacked (10, 11). Our c.m.r. analysis coupled with a careful integration of the p.m.r. methyl region (syn:anti ratio, 33 : 67) established the distribution of stereoisomers of this nitrosamine as 33% syn-axial, 41% anti-axial, and 26% anti-equatorial, as depicted in Fig. 2. No evidence of the syn-equatorial isomer could be found. These results allow us to assign 0.2 kcal/mol of greater strain energy4 to 4We consider only strain energy, as defined by Westheimer (13), since it is highly unlikely that other factors would contribute to thestability of amethylgroup in the various conformers. FRASER ET AL.: NITROSOPIPERIDINE CARBANIONS 2475