1.3- 477-Oxazines 5,6-dihydro-, conformation

The compounds with one double bond are dihydro-1,3-oxazines, and the structures shown in Fig. 1 are possible. The conformations of dihydro-1,3-oxazine rings arc based on analogy with cyclohexcne and also on the conformational analysis of several benzo-1,3-oxazine derivatives. 

In some cases, well-definable correlations could be demonstrated between the NMR data and the structural parameters of the 1,3-oxazine molecule. The magnitude of the 7-effects on the chemical shifts of 3,4-dihydro-277-1,3-benzoxazines 11 turned out to be influenced significantly by the substituents R attached to the nitrogen atom. A correlation between the Sq values and the steric substituent constants (its ) of the N-substituents proved useful in characterizing the variation of the 7-effects together with the conformational factors <1995STC77>. 

Both steric repulsion and anomeric effects proved to influence the conformational equilibria of 5,6-dihydro-4//-1,3-oxazines involving half-boat structures. For the /ra t-4,6-dialkyl-substituted compound 84, the conformational equilibrium was driven by steric repulsion it appeared that a 6-alkyl group in the axial position 84a is more hindered than an axial 4-alkyl 84b. However, for the /ra t, 6-diaryl-substituted derivative 85, the major conformation in the... 

The low temperature H-NMR spectra of 2-methyl-3,6-dihydro-2H-1,2-oxazine (239) gives a AG° favoring the /V-Meeq of 0.9 kcal mol", which is significantly less than that for the tetrahydro-l,2-oxazine (>1.9 kcal mol"1).246 This is similar to the decrease in conformational free energy of a methyl substituent on going from methylcyclohexane (1.7 kcal mol"1) to 4-methylcyclohexene (1.0 kcal mol 1),247 and the equilibrium 240 241 may represent a balance between lone-pair-Ti-bond repulsion in 240 and lone-pair-lone-pair repulsions in 241.246... 

For 2,6-disubstituted 3,6-dihydro-2/Z- 1,2-oxazines there are four energetically different half-chair conformations reflecting both ring and IV-inversion whereas for 3-substituted 3,4-dihydro-l//-2,3-benzoxazines there are only two conformers. 1H NMR studies do not... 

Of the two possible tautomeric structures for monocyclic dihydro-1,4-oxazines and -thiazines the 3,4-dihydro-2/f-representation is preferred in which the ring has a half-chair conformation. 

The reaction of 2-isopropyl-5,5-dimethyl-5,6-dihydro-2//-l,3-oxazine 306 with MCPBA leads to formation of the corresponding A -alkyl oxaziridine 307 as a single isomer <1995T139>. Due to the preferential conformation of imine 306, the imine double bond is exclusively oxidized anti to the f-propyl moiety. Oxidation of imine 308 with MCPBA gave oxaziridine nitroxide 309 in 90% yield <2000TL8787> and similar oxidation of 310 gave oxaziridine 311 in 74% yield <2005S1496>. 

For A-acyliminium ions that (can) adopt the s-cis conformation, the mechanistic picture is quite different. Now the /V-acyliminium intermediate reacts as a 4ir-electron component in a Diels-Alder cycloaddition with inverse electron demand (equation 28). " This process also shows high regio- and stereo-selectivity in most cases. A nice illustration of high stereospecificity is found in recent work on the intramolecular Diels-Alder reaction of A-acyliminium species (equations 29 and 30). The bis-amides (50) and (51) serve as precursors to the reactive intermediates, which cycloadd to the alkenes with high selectivity to give r/a s-fused bicyclic 5,6-dihydro-1,3-oxazines. 

The evidence from H NMR spectra of many 5,6-dihydro-47/-l,2-oxazines is that they adopt half-chair conformations (see Section 6.04.3.2) and this is supported by molecular mechanics calculations <90LA217>. 3,6-Dihydro-27/-l,2-oxazines also adopt a half-chair conformation <77JCS(P2)619>. 

Detailed conformational analyses were carried out for the 3,4-dihydro-l/7,6/7-[l,4]oxazino[3,4- ]quinazolin-6-ones (219). The oxazine ring of (219) assumes two equally populated, rapidly interconverting half-chair conformations. Substitution at position 1 resulted in the predominance of one of the conformers <93JHC1413>. The orientations of the hydrogens and the half-chair and chair-like conformations of the oxazinone moieties were demonstrated for the [l,4]oxazino[3,4- ]quinazoline (216) <80JHC1169> and the pyridazino[6,l-c][l,4]oxazinone (220) <87JCS(P1)2517>. 

A detailed study of the synthesis and conformation of stereoisomeric cis- and trans-tetramethylene- and -pentamethylene-dihydro-l,3-oxazines has been undertaken, e.g. (50). 3-Phenyl-4-hydroxy-2i/-l,4-benzoxazines, which may have some interest as antifungal agents, can be prepared as outlined in Scheme 109 4 jjjg hydroxylamines are rather unstable in air. 

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