Benz-l,4-oxazines

Data for the unusual pyrido[2,l-/i]benz-2,l-oxazine (27) <86LA69>, various pyrano[2,3-/]quinazo-lines (28) <87JHC603>, pyrano[l,4]benzoxazines (29) <71JCS(C)2079), and Reissert-type phosphonates of 1,7-phenanthroline <86BCJ2362> have been reported. 

Fig. 5. Proposed mechanism of inactivation of a-chymotrypsin by the pseudoirreversible inhibitor 2-ethoxy-4.H-3,l-benz-oxazin-4-one. A substituted...

The reaction of 1,3-disubstituted perhydropyrido[l,2-c][l,3]oxazines (69) and 7-(benzothiazol-l-yl)-6,7-dihydro-17/,3//,5//-pyrido[3,2,l-iy][3,l]benz-oxazine with Grignard reagents led to 2-(/V-substituted 2-piperidyl)ethanols (70) (50JA358 58CLY2081) and l-benzyl-4-(benzotriazol-l-yl)-8-hydroxy-methyl-l,2,3,4-tetrahydroquinoline (95JOC3993), respectively. 

An expedient montmorillonite KIO day-catalyzed cydoisomerization of sali-cylaldehyde 4-(yS-D-ribo- or j8-D-2 -deoxyribofuranosyl)semicarbazones yields benz-oxazinone nucleosides, 4-hydrazino-3,4-diliydro-3-(j8-D-ribo- or j8-D-2 -deoxyri-bofuranosyl)-21-f-benz[e]-l,3-oxazin-2-ones, which readily undergo reductive dehydrazination on alumina-supported copper(II) sulfate to furnish 3,4-dihydro-3-(jS-D-ribo- or yS-D-2 -deoxyribofuranosyl)-2H-benz[e]-l,3-oxazin-2-ones under the action of microwave irradiation (Scheme 8.37) [105]. The reaction is solvent-free. 

Good yields of 2H-benz[e]-l,3-oxazin-2-ones were obtained by qfdization of salicy-laldehyde semi-carbazones catalyzed by day Kio under irradiation conditions (Scheme 10.111) [218]. 

More recently, the same group reported an analogous cyclization for the synthesis of 21-f-benz[e]-l,3-oxazine-2-thiones [219] and functionalized 1,3-thiazines [220]. 

S)-6-Chloro-4-(cyclo-propylethynyl)-l,4-dihydro-4-(trifluoro-methyl)-2H-3,l-benz-oxazin-2-one (Efavirenz DMP-... 

Dehydrazinative cyclization of salicylaldehyde semicarbazones 444 was affected under solvent-free conditions on montmorillonite Kio using MWI to give 2H-benz[e]-l,3-oxazin-2-ones 445 in 83-94% yields within 1.5-3min (Scheme 87). Employing conventional heating in an oil bath, this cyclization could not be completed (only 60% conversion) after 20h (02TL8551). 

Ice-cooled HCl-satd. nitromethane added with swirling to a soln. of 3-tert-huXy -oxycarbonyl-l,4-dioxo-3,4-dihydrobenz[d] [l,2]oxazine -> l,4-dioxo-3,4-dihydro-benz[d][l,2]-oxazine. Y 80%. G. Zinner et al., Synthesis 1971, 148. 

The last decade has brought a considerable increase of the number of papers concerned with 1,3-oxazine derivatives. This is due partly to the fact that these compounds show interesting reactivity. Hence, it was suggested recently that 1,3-oxazine derivatives (including benz-l,3-oxazine derivatives) should be used as chemotherapeutic agents. ... 

Benz[l,2-e][l,3]oxazin[3,4-a]azepin-6-one (15) is cleaved rapidly in cold ethereal ethylamine to /V.A-diethyl-2-(2-hydroxyphcnyl)-l//-azepinc-1-carboxamide (90% mp 121 -122°C), whereas acidic hydrolysis yields the intramolecularly hydrogen bonded 2-(2-hydro-xyphenyl)-3//-azepine (16).156... 

Almost complete retention of chirality was achieved in the alkylations of l-propionyl-l,4-dihydro-2//-3,1-benz-oxazines 242 bearing a stereogenic center in the substituent at position 2 (TBDPS = /< rt-butyldiphenylsilyl, KHMDS = potassium hexamethyldisilazide). The alkylations took place with high de s (70-92%) in favor of isomers 243, isolated after chromatographic separation. The allyl-substituted compound 243 (R = allyl) was reduced with LAH to yield the enantiopure (R)-3-methylpent-4-en-l-ol 244 and the N-unsubstituted 3,1-benzoxazine 245 as a 5 1 diastereomeric mixture (Scheme 45) <2000JOC6540>. 

Although 2-//-l,2-oxazines are unstable, the 1,3-isomers are quite well known. The 1,4-oxazines are relatively uncommon and unexplored. Aspects of the halogenation of oxazines and thiazines have been summarized (84MI14). Much more is known about the sulfur analogues, especially the benz derivatives of 1,4-thiazine (see Part 3). When perfluorinated 1-chloro-1,2-thiazine was heated with potassium fluoride, the chlorine was replaced by fluorine (92CB581). 

Quaternary salts (43) form benz-l,3-oxazines (44).64,85 The reaction has been formulated as proceeding through ylids (45) and ring-opened... 

A new synthesis of 2,4,4,6-tetramethyl-4//-l,3-oxazine (155) simply involves a reductive cycloaddition of 4-methylpent-3-en-2-one and acetonitrile in the presence of trimethylsilyl chloride and sodium iodide (Scheme 42) <89TL4741>. Other cycloaddition reactions have been used previously to synthesize 4//-l,3-oxazines and this methodology has been extended to include cycloadditions between alkynes and l-oxa-3-azabuta-1,3-dienes. For example, phenylethyne and the A-benz-oylimine (156) afford 4,4-bis(trifluoromethyl)-2,6-diphenyl-4//-l,3-oxazine (157). The reaction proceeds through a Michael-type addition between the alkyne and the heterodiene giving an adduct which when heated to 80-90°C cyclizes to the oxazine (Scheme 43) <83CC945,89ZN(B)1298>. 

Pyrrolidinocyclohexene added drop wise at 0° under Ng (maintained throughout the reaction) during a few min. to a soln. of 2-nitro-l-phenylpropene in dry hexane, then allowed to warm to troom temp., and the product isolated after 2 hrs. -> 3-methyl-4-phenyl-8a-pyrrolidino-4a, 5,6,7,8,8a-hexahydro-4H-l, 2-benz-oxazine 2-oxide. Y 91%. F. e. s. A. T. Nielsen and T. G. Archibald, Tetrahedron 26, 3475 (1970). 

Salicylic acid chloride heated 3 hrs. in dry benzene with N-benzylidene-4-methylaniline 2,3-dihydro-2-phenyl-3- (4-methylphenyl) -4-oxo-4H-l,3-benz-oxazine. Y 92%. F. e. s. E. Ziegler and H. D. Hanus, M. 96, 411 (1965). 

A soln. of 4-amino-3-hydroxy-5-methylacetophenone and the equivalent amount of diethyl oxalacetate refluxed 1 hr. ethyl 5-methyl-7-acetylbenz-l,4-oxazin-2-on-3-ylacetate. Y ca. 90%.—Because these benz-l,4-oxazin-2-ones crystallize well and can be cleaved by alkali, they are suitable for the separation of aminophenols and the identification of the o-isomers. Even isomeric o-aminophenols can be separated due to different reaction rates. F. e. s. A. Butenandt, E. Biekert, et al., B. 92, 2172 (1959). Condensed l,4-oxazin-2-ones may also be used for the identification of a-ketocarboxylic acid esters. E. s. B.94, 1664 (1961). 

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