Dihydro-1,3-oxazines hydrolysis

Acidic hydrolysis of 2-trichloromethyl-5,6-dihydro //-oxazine derivatives gave the corresponding amino alcohols in high yields <1996GC355, 1997TL607, 1998CC761>. 

The only known derivative of this class was prepared from ethyl 8-anilinecrotonate, ethyl acetoacetate, and benzaldehyde. In the first instance, a pyrimidine derivative is formed, this is then subjected to partial hydrolysis to form the 3,4-dihydro-l,3-2H-oxazine derivative (42). 

Alkaline hydrolysis of of 5,6-dihydro //-l,3-oxazines is a convenient method via which to obtain the corresponding 1,3-amino alcohols or their A -acyl derivatives <1996CC1629>. The yields are usually excellent, as in the transformation of 2,4,4-trimethyl-5,6-dihydro //-l,3-oxazine 130 to 3-amino-3-methylbutan-l-ol 131 (Equation 11) <2001JLR265>. 

No loss of optical purity was observed in the mild acidic hydrolysis of the enantiomerically pure 6-alkoxy -phenyl-5,6-dihydro-4/7-l,3-oxazine 132, which resulted in formation of (R)-3-benzoylamino-3-phenylpropanal 133 in excellent yield (Scheme 20). Hydrolysis of the analogous tetrahydro-l,3-oxazin-2-one 134 to 133 required a stronger acidic medium and took place only in poor yield, but without any decrease in the optical purity <20000L585, 2003JOC4338, 2004TL9589>. 

Kinetic resolutions by means of the selective formation or hydrolysis of an ester group in enzyme-catalyzed reactions proved to be a successful strategy in the enantioseparation of 1,3-oxazine derivatives. Hydrolysis of the racemic laurate ester 275 in the presence of lipase QL resulted in formation of the enantiomerically pure alcohol derivative 276 besides the (23, 3R)-enantiomer of the unreacted ester 275 (Equation 25) <1996TA1241 >. The porcine pancreatic lipase-catalyzed acylation of 3-(tu-hydroxyalkyl)-4-substituted-3,4-dihydro-2/7-l,3-oxazines with vinyl acetate in tetrahydrofuran (THF) took place in an enantioselective fashion, despite the considerable distance of the acylated hydroxy group and the asymmetric center of the molecule <2001PAC167, 2003IJB1958>. 

Cycloaddition of a-nitroso acrylic esters (749) to alkenes followed by base hydrolysis provides a route to 5,6-dihydro-4//-l,2-oxazine-3-carboxylic acids (750). These heterocycles on heating above 150 °C decarboxylate to furnish y-hydroxynitriles (thus the overall c/s-addition of OH and CH2CN to a double bond), which can be transformed further to y-lactones (751) by treatment with methanolic hydrochloric acid (Scheme 172) (79CC1090). The adducts were also reduced to a-amino esters (752) by the action of aluminum amalgam (Scheme 173) (79CC1089). 

Monocyclic systems of this type are poorly represented in the literature and so far only two routes to 3,4-dihydro-2/f- 1,3-oxazines have been described which may be capable of further development. The first depends upon the interconversion of the tetrahy-dropyrimidine (192) into the oxazine (193) by partial hydrolysis, and the second requires the acid-catalyzed condensation of benzaldehyde with the /3-amino ester (194 Scheme 80) (4SJA1382). 

Reaction of diacetatoboron chelate 198 with cyclic amines (09USA2009/0156577), 2-aminomethylaziridine (06CCL1431), followed by hydrolysis provided 10-substituted 3(S)-methyl-9-fluoro-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4]oxazine-6-carboxylic acids. 

Cationic polymerization of unsubstituted 4-membered cyclic amine proceeds in a way similar to that of aziridine, giving branched polymer containing, according to H NMR, 20% of primary, 60% of secondary, and 20% of tertiary amino groups [174]. Purely linear polymer can be obtained by polymerization of 5,6-dihydro-4H-l,3-oxazine, followed by hydrolysis [175] ... 

Synthesis of ketones. The dihydro-l,3-oxazinc system itself is inert to Grignard reagents. Meyers and Smith now report that oxazines (1) form. stable N-methyl quaternary iodides (2) when treated with excess methyl iodide. These react with Grignard reagents (2-2.5 cq.) at room temperatures to give an adduct (3), which on hydrolysis with aqueous oxalic acid yields the ketone (4) and the amino alcohol (5). 

Several related reactions involve reduction of cyclic carboxylic acid derivatives to masked aldehydes which resist further reduction but can be converted into the required aldehydes by acid hydrolysis. In a series of papers, it was established that carboxylic acids could be converted into dihydro-1,3-thiazines or dihydro-1,3-oxazines which could be reduced by NaBH4 in weakly acidic ethanol. Thus, as shown in Scheme 20, dihydro-1,3-thiazines (41) were reduced to tetrahydro-1,3-thiazines (42) in yields of 66-84%. The resulting tetrahydro compounds could be hydrolyzed to aldehydes by aqueous acid. - In a later publication, these workers showed that there was little evidence for ring opening during reduction and that other methods of reduction e.g. hydrogenation over Pt, Pd or Rh or use of dissolving metals such as Zn, Sn or Na) were totally unsuccessful. In closely similar work, reduction of 5,6-dihydro-4W-... 

Much interest lies in the use of dihydro-1,3-oxazines (190) as enolate equivalents, since, if an alkyl group is carried at C-2, these compounds may be deprotonated and the anions formed reacted with numerous types of electrophiles. Reduction of the imine bond of the products (191), is then conveniently effected by treatment with sodium borohydride. The tetrahydrooxazines (192) which are formed may then be ring opened by hydrolysis with aqueous acid (Scheme 15). This topic and its utility in synthesis has been well reviewed. - ... 

The dihydro-1,3-oxazine route has been extensively investigated by Meyers. Controlled reduction to the tetrahydro derivative (53), followed by hydrolysis, gave good yields of the corresponding aldehyde or deuteriated aldehyde, R—CDO (Scheme 22). ° Further development of this concept has subsequently given rise to convenient routes to acyclic, a,3-unsaturated, ° alicyclic, y-hydroxy and y-oxo aldehydes. Full synthetic details of these and other variants of the Meyers aldehyde synthesis have been published. ... 

Stork overcame the dialkylation problem at the a-carbons in aldehydes by using imines. The obvious disadvantages of this method are the unstable starting materials (Schiff bases). Meyers and coworkers found that the stable commercial starting material 2,4,4,6-tetramethyl-5,6-dihydro-l,3-4A/-oxazine 43 can be used as a precursor for formation of various aldehydes. After lithiation of the methyl group in the 2 position it acts as an excellent nucleophile in reaction with various electrophiles E, and after reducing the double bond and hydrolysis the aldehyde group is formed (equation 15). 

Synthesis of carboxylic acids. Dihydro-1,3-oxazines are hydrolyzed by aqueous hydrobromic acid to carboxylic acids.6 This fact, coupled with the fact that this ring system is completely inert to Grignard derivatives, forms the basis for a new synthesis of carboxylic acids.7 Thus 2,4,4,6-tetramethyl-5,6-dihydro-1,3-(4H)-oxazine (1) is alkylated with 1,5-dibromopentane to produce (2). This is converted into the nitrile (3), then the phenyl ketone (4) finally acid hydrolysis gives 7-benzoylheptanoic acid (5). 

Synthesis of ketones. 5,6-Dihydro-1,3-oxazines are also useful for synthesis of ketones.9 Thus the 2-isopropenyl oxazine (l)10 reacts in THF with Grignard or organolithium reagents to give a 2,2-dialkyltetrahydro-l,3-oxazine (2), which on hydrolysis with oxalic acid gives an a-methyl ketone (3). An important feature of... 

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