Oxazines tautomerism

Isoxazol-3-ol, 5-methyl- — see Hymexazoi Isoxazoi-5-ones 3,4-disubstituted synthesis, 6, 64 5-substituted tautomerism, 6, 11 synthesis, 6, 64 Isoxazolo[2,3-h][ 1,2]oxazines synthesis, 6, 633 Isoxazolophanes... 

H-1,2-Oxazine, 3,6-dihydro-6-(2-pyridyl)-mass spectra, 2, 529 2H-1,2-Oxazine, tetrahydro-synthesis, 2, 92 4H-l,2-Oxazine, 5,6-dihydro-pyrolysis, 3, 999 synthesis, 3, 1017 tautomerism, 3, 999 4H-1,2-Oxazine, 5,6-dihydro-3-methyl-metallation, 1, 484 4H-l,2-Oxazine, 5,6-dihydro-3-nitro-reactions, 3, 1000 6H-l,2-Oxazine, 3,5-diphenyl-stability, 3, 997 synthesis, 3, 1014... 

By tautomerism the product can also be regarded as a 5,6-dihydro-l,3-4//-oxazine derivative (28b). 

Dihydro-2/7- 74 and -4//-l,2-oxazines and thiazines 75 are interrelated by prototropy, being enamines and imines, respectively. In the case of oxazines, the imine form 75 is favored, and there are several well established examples of this system, including the parent heterocycle 75 (X = O) [84MI2]. No tautomeric equilibrium between the 2H and 4H forms has been observed under normal conditions in solution or in the solid state. However, the formation of intermediate 2H isomers 77 was proposed both for the conversion of 3-phenyl-5,6-dihydro-4//-l,2-oxazine 76 (R = Ph, r = R = H) into 2-phenylpyrrole(89TL3471) under strong basic conditions and for thermal decomposition of cyclopentene-fused 1,2-oxazine 76... 

Representatives of all three types of isomeric 1,3-oxazines 82-84 (X = O) and 1,3-thiazines 82-84 (X = S) and of the corresponding partially hydrogenated derivatives are known. However, no tautomeric interconversions between these structures have been observed. 

Few monocyclic 1,4-oxazines are known and their chemistry is relatively unexplored no systematic studies on the possible annular tautomerism of these compounds have been undertaken. However, it was shown that benzo-fused 1,4-oxazines 85 (R = H, Me, R = SMe R = R = COR) exist exclusively in the 2H form and do not tautomerize under normal conditions (76AHCS1, p. 80 80JHC1625). 

The iV-unsubstituted 2-aryltetrahydro-l,3-oxazines exhibit ring-chain tautomerism in solution. Depending on the steric and electronic characters of the substituents, the ring form and the open-chain Schiff base form occur in different ratios. For a more detailed discussion, see Section IV,A,4. 

The presumed mechanism of the oxidative ring enlargement is shown for 52 (R = Ph). The first step is the oxidation of the isoxazolidine to the unstable N-oxide 58, which rearranges to the unstable dipolar 59 this yields the methylene nitrone 60 by tautomerization. 60 gives oxazine 53, through ring-chain tautomerization (79JOC1819). 

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... 

Amidation of W-BOC-tetrahydro-l,2-oxazine-6-carboxylic acid 47 with free oxanipecotic acid afforded amide 48 <2003TL3447>. The 3-methyl-substituted 1,2-oxazine Woxide 280 can be selectively transformed into 2-silyloxy-1,2-oxazines 281, upon treatment with silylating reagents (ClSiMe3). Now, the synthetic utility of 2-silyloxy-l,2-oxazine 281 is extended and it can be rearranged into 3-silyloxymethyl-l,2-oxazine 282 and can further react with morpholine to produce 3-morpholinomethyl-l,2-oxazine 283 which exists in a tautomeric equilibrium with the corresponding open-chain oxime <2003JOC9477>. 

The NMR spectra of the as- and /ra r-cyclohexane-condensed 1,3-oxazine derivatives 27 exhibited no sign of tautomeric equilibria between the imino and amino forms, but all four compounds appeared to attain (at least almost) exclusively the 2-imino-l,3-oxazine form 27A <2003MRC435>. 

For the tautomeric equilibria of perhydro-l,3-oxazines and their benzo derivatives bearing an X-substituted phenyl group at position 2, the proportion of the ring-closed forms has been found to be strongly dependent on the electronic character of the substituent X on the phenyl ring. For these compounds, a linear correlation (Equation 1) has been found between the log values of the equilibria (Xx= [ring]/[chain]) and the Hammett-Brown parameters of the substituents X on the 2-aryl group ... 

To characterize the electronic and steric effects of the substituents at positions 4-6 on the stability of the 2-aryl-l,3-oxazine ring forms exhibiting ring-chain tautomerism, a relative ring stability parameter (c) has been introduced. The value of c is calculated as the difference between the value of log Xx = h for a 2-aryl-l,3-oxazine derivative bearing substituents at positions 4-6 and the intercept value (log Xo = —0.15) for the parent unsubstituted 2-arylperhydro-l,3-oxazine (c = log Xx = h log Xq). 

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