Tetrahydro-1,3-oxazines, ring chain

The ring-chain tautomerism of tetrahydro-l,3-oxazines is very sensitive to the stability differences, the substituents and the ring-fusion effect (Section IV,A). It also reveals a considerable stability difference in favor of the cis isomers. In the reactions of the cis- and trans-2-amino-l-cyclohexanols, as compared with the hydrindane analog systems, where the heteroatoms form an oxazolidine ring cis- or tra 5-fused with cyclohexane, the corresponding stability differences were again found to be in favor of the cis isomer (93JOC1967). 

The ring-chain tautomerism of tetrahydro-1,3-oxazines, which involves the reversible addition of a hydroxy group to a C = N bond, is a well-established process and was reviewed recently [94ACH(131)697 95AHC(64)251 96AHC(66)1]. In this context, only the most important characteristics of the ring-chain tautomerism of the alicycle-fused 1,3-oxazines is briefly discussed. 

The tautomerism of the 2-aryl-substituted tetrahydro-1,3-oxazines with the general structures 390, 391, 393, 394, and 396-406 has been studied in detail. Only the structures of the ring forms are shown. In all series, the ring-chain tautomeric equilibria measured in CDCl.i at room temperature can be described by the equation... 

Reduction of cycloalkane-condensed 2-phenyl-5,6-dihydro-4//-l,3-benzoxazines 144 with lithium aluminium hydride (LAH) afforded A -benzyl-substituted 2-(aminomethyl)cycloalkanols 145 in a reductive ring opening via the ring-chain tautomeric tetrahydro-l,3-oxazine intermediates. Catalytic reduction of 1,3-oxazines 144 under mild conditions in the presence of palladium-on-carbon catalyst similarly resulted in formation of the A -benzyl-1,3-amino alcohols 145. When the catalytic reduction was performed at elevated temperature at hydrogen pressure of 7.1 MPa, the N-unsubstituted 2-(aminomethyl)cycloalkanols 146 were formed in good yields (Scheme 22) <1998SC2303>. 

Because of their ring-chain tautomeric character, tetrahydro-l,3-oxazines can be used as aldehyde sources in acid-catalyzed condensation reactions involving the carbon transfer via the open forms. This approach is especially advantageous in those cases where the aldehydes required for the condensations are unstable or difficult to access <2003EJ03025>. 

The condensation of 3-aminopropanol 371 with formaldehyde and ethyl phenylphosphinate or diethyl phosphite afforded the corresponding (tetrahydro-l,3-oxazin-3-ylmethyl)phosphinate 391 (R = Ph) or phosphonate 391 (R = OEt) derivative (Scheme 73). These condensations probably take place via addition of the phosphite/phosphinate to the C=N bond of the open form of the ring-chain tautomeric tetrahydro-l,3-oxazine intermediate 390 <2006HAC75, 2006HAC81>. 

Meyers et al.221-222 showed that tetrahydro-l,3-oxazines exist in tautomeric ring-chain forms [Eq. (62)]. When a 5,6-dihydro-l,3-oxazine is reduced to a tetrahydro-l,3-oxazine, some 3-aminoalcohol can also be formed through the reduction of the open-chain imino form [cf. Eq. (62)]. To avoid this the reduction should be carried out with sodium borohydride at - 40°C. 

The ratio of 33A and 33B proved to be slightly solvent-dependent (Table V). The reactions of 3-amino-l,2-propanediol with substituted aromatic aldehydes in CDC13 resulted in five-component ring-chain tautomeric equilibria. Besides the open-chain form 34A, two epimeric oxazolidines (34B and 34B ) and two epimeric tetrahydro-l,3-oxazines (34C and 34C ) were identified in the tautomeric mixture. The proportions of the tautomers in the equilibrium for X = p-NC)2 were [34A] [34B] [34B ] [34C] [34C ] = 40.7 7.0 5.9 9.7 36.7 (94MI1, 94MI2). 

N-Methyl-tetrahydro-l,3-oxazine exists as a mixture of ring and open-chain tautomers in TFA the analogous oxazolidine behaves similarly. Of interest is the fact that ring-chain interconversion is more rapid for the oxazolidine, in converse to the predictions of Baldwin s vectorial rules. 

The main ring syntheses of tetrahydro- 1,3-oxazine derivatives are summarized by diagrams a to d (Fig. 1). Two additional methods comprise the cyclization of six-membered chains, and the hydrogenation or... 

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