1.IntroductionThe oxazines are cyclic compounds generated from the substitution of two atoms of carbon in the cyclohexane, for a nitrogen atom and one of oxygen. These substitutions distort the chair conformation which is commonly observed as the most stable structure in cyclohexane and related derivatives.Since the 1950s oxazinic derivatives have attracted the attention of researchers for two reasons, their pharmacological activity,1,2and their reactivity and molecular structure.3,4Examples of its powerful biological activity are given in the works by Urbanskiet al.1aand Ecksteinet al.,1bwhich gave evidence for the cytotoxic activity and antitumor properties of 5-nitrotetrahydro-1,3-oxazine derivatives. Other examples are the antileukemic antibiotics macrolides such as Maytansine, Maytanprine and Maytanbutine with tetrahydro-1,3-oxazine-2-one structures,2andMaytenus ovatus,Maytenus buchananiiandMaytenus serratastudied by Meyerset al.1cFrom the structural point of view these derivatives represent a convenient example to study both the conformational effect of introducing heteroatoms into the ring and the preferred orientation of the alkyl group attached to nitrogen in the heterocycle. For this reason, the 1,3-oxazines have been studied and a considerable amount of experimental data on these compounds already exists.3Among the first studies is the work done by Urbanskiet al.4awho concluded that this type of heterocycles exhibit a chair conformation and that the nitro group is preferred in the axial position. Eliel and co-workers4bconfirmed this observation. Allinghamet al.3dthrough a NMR analysis extended previous studies4ato then-propyl, isopropyl and cyclohexyl derivatives. The1H NMR data allowed determining the preferential conformation by studying theJgemfor C2, C4 and C6 protons. These coupling constants would be sensitive to orientation of the nitrogen lone-pair, and showed that methyl, ethyl and propyl substituents must exist predominantly in axial conformation whereas isopropyl andtert-butyl substituents are predominantly in equatorial conformation. Factors such as electronic delocalization, electrostatic repulsions and steric factors, are the predominant ones dictating the most stable nitrogen conformation.5Few papers have reported the percentage of a given conformer in the chemical equilibrium of 1,3-oxazines. Katritzky and co-workers6found that ΔGo138isca.−0.16 kcal mol−1for the equatorial–axial equilibrium in 3-methyl-1-oxa-3-azacyclohexane, the dominant component being that having an axial methyl group. Also, Lehn and Riddell3emeasured the axial–equatorial free energy differences for N-methyl in tetrahydro-1,3-oxazines series. The aim of this work is to show that1H chemical shifts can be used to determine the percentage (α) of each conformer in the chemical equilibrium. For this purpose we shall use the experimental chemical shift measured by Allinghamet al.3dto determine theαparameter which will be compared with that obtained from the theoretical calculation of free energy assuming a Boltzmann distribution.We have considered also interesting to calculate the nitrogen inversion barrier for each of the compounds included in this study, since it seems well established that for multiheteroatom six-membered rings the ring inversion barrier is higher than the nitrogen inversion barrier, provided the heteroatoms are not adjacent.7Very few works3f,6,8regarding the nitrogen inversion barrier in oxazinic rings, have been reported in the literature. In this respect is worth mentioning the work of Lehnet al.,3fin which the nitrogen inversion barrier on non-nitrate oxazines was investigated by means of variable-temperature NMR techniques.