1.4- Oxazines, tetrahydro-, conformation

Experimentally, it has been shown that the introduction of a heteroatom such as oxygen into the 4-position of piperidine has no appreciable influence on the conformational equilibrium348. Similarly, infrared overtone measurements suggest that in tetrahydro-1,2 oxazine the NH-equatorial conformer predominates349. On the other hand, many piperidines substituted by heteroatoms in the 3 position are found to exhibit a NR axial preference. For example, the preferred conformation for the molecules shown below is NR axial350,35... 

The conformational analysis of methyl-substituted tetrahydro-1,3-oxazines has been discussed in detail in several contexts (86MRC145,... 

For determination of its configuration via a conformationally restricted cyclic derivative, A -allylamino alcohol derivative 475 was treated with tris(triphenylphosphine)rhodium(l) chloride to afford a 19 1 mixture of the C-2-epimeric tetrahydro-l,3-oxazines 476 and 477 by intramolecular trapping of the intermediate iminium species, in equilibrium with the enamine generated in the isomerization of the allyl double bond (Equation 52) <1997CC565>. 

The low temperature H-NMR spectrum (CD2C12, — 40°C) of 2,5-dimethyltetrahydro-1,2-oxazine (equilibrium shown in Fig. 10) shows an equilibrium between 229 (95%) and 232 (5%).239 The N-Meax conformers 230 and 231 are neglected because even tetrahydro-1,2-oxazine itself exists exclusively as the /V-Heq conformer,237 and calculations on hydroxylamine indicate a very high energy for conformations that correspond to axial N-substituents.240 Thus the conformational free energy of the 5-methyl group may be estimated as 1.36 0.1 kcal mol -1 at —40°C.239... 

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... 

Dipole-moment measurements indicate 62% N-H-axial for tetrahydro-1,3-oxazine and 74% (V-H-axial for 5,5-dimethyltetrahydro-l,3-oxazine,269 but these estimates could well be low. The predominant /V-H-axial conformation is clearly demonstrated by the IR spectrum in the first overtone N-H... 

Dipole-moment measurements were interpreted as favoring the N-alkyl equatorial conformation for a range of N-alkyl tetrahydro-l,3-oxazines, giving 58% eq N-Me, 68% eq N-Et, 86% eq AMPr and 100% eq N-t-Bu,271 but these conclusions can no longer be regarded as reliable. 

Following the trend observed for the oxazine analog 296, the fusion of a benzene ring onto the [/] position of perhydropyrido[l,2-c][l,3]thiazine, as in 1,6,7,116-tetrahydro-2//,4//-[l,3]thiazino[4,3- ]isoquinoline 316, pushes the equilibrium almost exclusively to the S-inside cis conformation 317.284... 

The conformational equilibria for tetrahydro-1,4,2-dioxazines (425) should combine the characteristic features of the equilibria for tetrahydro-l,3-oxa-zines (Section III,D,1) and tetrahydro-l,2-oxazines (Section III,C,1). Thus by analogy with the 3-methyltetrahydro-l,3-oxazine equilibrium (AG° N-Meeq N-Me -0.10 0.05 kcal mol"1 at -120°C, Table XX), in the... 

The conformational equilibria in TV,V-dimethy 1 tetrahydro-1,2,5-oxadia-zine 451 (Fig. 21) may be considered with reference to those of the N-methyl-tetrahydro-l,2-oxazine system (Section III,C,1) (for which AG° 3.7 kcal mol-1 favors W-Meeq) and the (V-methyltetrahydro-1,3-oxazine system (Section III,D,1) (AG° 0.1 kcal mol-1 favors A/-Meax). Hence the 2-N—Me group should be predominantly equatorial and the 5-N—Me should show a small preference for the axial orientation. 

X-Ray crystallographic analyses show that tetrahydro-l,2-oxazines adopt a chair conformation, although the ring is considerably more puckered than that of cyclohexane. The lone pair electrons of IV-methyl derivatives assume an axial orientation and in the case of 2,5-dimethyl compounds the trans conformer is strongly preferred (75T523). 

Tetrahydro-l,3-oxazines are normally assumed to adopt a chair conformation in which the NH bond has an axial orientation. This view is substantiated by NMR spectroscopy and also by dipole moment analysis <73JCS(P2)325). The ring system is not stable and, for example, when the parent molecule is allowed to stand, it slowly ring opens and then forms a trimer (Scheme 33) (78AF937). In acidic media ring fission is accelerated and the open-chair imines may then hydrolyze. This property has been utilized in the synthesis of aldehydes as previously noted (see Section 2.27.2.2.4(0). 

Investigations of the conformational analysis of 5-alkyl-5-nitro-tetrahydro-l,3-oxazines by dipole moments1 have been extended to derivatives with various substituents in positions 3 and 5.281-282 They... 

Since the advent of NMR as a tool for conformational analysis, a number of papers have been dedicated to conformation of tetrahydro-1,3-oxazine in addition to those mentioned above. Nevertheless, conclusions based on coupling constant measurements are valid only for closely related compounds.289... 

The conformations of the 2-oxo-tetrahydro-l,3-oxazines obtained from phosgene and the isomeric 3-amino-2,3-diphenylpropanols were used by Fodor et al. as an ingenious criterion for the configurational determination of the aminopropanols.13,14 The erythro form yielded an oxazinone that showed optical activity 4-8 times stronger than that from the threo form. 

NMR studies at low temperature strongly suggest that, in tetrahydro-1,3-oxazine, conformer 91 (R=R =H) makes the major contribution to the equilibrium 91 92 (66). The same conclusion was reached for the case where R=CH3 and R = H. Two anomeric effects are possible in conformer 91 and only one in conformer 92 the greater stability of 91 can therefore be rationalized by the extra anomeric effect of the nitrogen atom. 

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