DEPROTONATION OF 5,6-DIHYDRO-5-METHYLENE-4H-1,2-OXAZINES AND REGIOSELECTIVE REACTIONS WITH ELECTROPHILES

5,6-Dihydro-5-methylene-4H-1,2-oxazine 1 is smoothly converted by n-butyllithium inot 1-Li which reacts with electrophiles such as D2O, carbonyl compounds, dimethyl sulfide, or an azo diester to give the gamma-adducts 4a-4f. On the other hand, alkylation of 1-Li occurs exclusively at C-4 of the heterocycle and provides the alpha-adducts 3g and 3h. These reactions require the activation of 1-Li by tetramethylethylenediamine. Treatment with allyl bromide and methyl acrylate affords mixtures of regioisomers 3 and 4. 1,2-Oxazine 5 with a conjugated C = C bond is less acidic than 1 but is also converted into 1-Li, whilst compound 6, lacking the 6-methoxy group, is not deprotonated under standard conditions. The dianion of 1,2-oxazine 7 is generated by employing an excess of n-butyllithium. This dianion displays a similar regiochemical behavior as 1-Li. Deuterium is exclusively incorporated into the gamma-position to give product 8, while methylation occurs at C-4 to produce 9. 1,2-Oxazine 3g with an additional 4-methyl group can also be metalated and affords gamma-adducts 10 and 11 upon reaction with D2O or acetone. Treatment with methyl iodide gives a 3:1 mixture of regioisomers 12 and 13. Deuteration of 1,2-oxazines 14 and 16 bearing a 3-CF3 or 3-CO2Et substituent requires more severe deprotonation conditions to provide the gamma-adducts 15 and 17 in moderate yields. MNDO calculations of neutral 1,2-oxazines, the corresponding carbanions, and the lithium compounds allows an insight into the structure and charge distribution of these species, and also an estimation of the relative acidities. The regioselectivity of reactions of 1-Li is discussed on the basis of these semiempirical calculations and comparison with related ambident nucleophiles.