Methyl substituted tetrahydro-1,3-oxazines

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

Lithium aluminum hydride reduction of tetrahydro-l,3-oxazin-2-ones 434 results in the corresponding A -methyl-substituted 1,3-amino alcohols 435 (60JA4656 87TL1623). 

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>. 

When heated at 230 °C, tetrahydro-l,3-oxazines 173, bearing an a,/3-unsaturated ester substituent at position 2, underwent a retro-ene reaction and yielded 5,6-dihydro-477-l,3-oxazines 174 together with methyl 4-methyl-3-pentenoate 175 (Equation 16). For the methyl-substituted oxazine 173 (R = Me), the yields of both products were somewhat higher than those in the reaction of the unsubstituted analog 173 (R = H) <1997JHC501>. 

N-substituted tetrahydro-1,3-oxazines were also studied. It has been suggested (66) that conformer 93 with the M-alkyl group in the axial orientation, is more stable than 94 when R is either a methyl or a benzyl group. It was also found that the contribution made by conformer 95 is appreciable and it may dominate conformer 96 in tetrahydro-3,4,4,6-tetramethyl-l,3-oxazine. 

The tetrahydro-l,3-oxazines which contain a free A -hydrogen atom can be iV-acylated and A -nitrosated. - Certain A-substituted derivatives of tetrahydro-l,3-oxazin s can also react with acetic anhydride to form A -acetyl derivatives. > Most tetrahydro-l,3-oxazines add methyl iodide to form quaternary... 

The A -acyl derivatives of 4-substituted-3,4,5,6-tetrahydro-27/-l,3-oxazin-2-ones proved to behave as effective chiral auxiliaries in asymmetric enolate alkylations and aldol reactions, the stereoselectivities of which were found to be higher for 4-isopropyl than for 4-phenyl derivatives <2006OBC2753>. The transformations of 4-isopropyl-6,6-dimethyl-3-propa-noyl-3,4,5,6-tetrahydro-2/7-l,3-oxazin-2-one 251 to 252 or 253 proceeded with excellent diastereoselectivities (Scheme 47). 6,6-Dimethyl substitution within the oxazine ring facilitated exclusive exocyclic cleavage upon hydrolysis of the C-alkylated and the aldol products 252 and 253, to furnish a-substituted carboxylic acids 254 or a-methyl-/ -hydroxycarboxylic acids 256. 

A 7-substituted 3,4,6,7-tetrahydro-2//-pyrido[2,l-h][l,3]oxazine was formed as by-product the alkylation of methyl 2-(benzyloxycarbonyl-6-oxo-l-phenylsulfonyl)indol-2-yl)-2-azabicyclo[2,2,2]octane-6-enrfo-car-boxylate with 3-iodopropanol from a 3-substituted l-(3-hydroxypropyl)-2,3-dihydropyridinium intermediate (90JOC6028). 

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