4//-l,2-Benzoxazines

Oxidative cyclization of the 2-(morpholinomethyl)phenol 394 by use of Pb02 resulted in the 1,3,4,11 -tetrahydro-6/7-[l,4]oxazino[3,4+][l,3]benzoxazine 388 along with a dimeric minor product 395 (Equation 45). The structure of 388 was supported by X-ray crystallography <1997RCB1272>. 

Japanese researchers varied aryl substituent at C-4 in nitronate (147), LA, and the reaction conditions, they used successfully diastereomerically pure nitronates (147) (Scheme 3.121) for the synthesis of various fused-ring systems, such as benzofuro-[3,2-d]-l,2-oxazines (322), furo-[3,4-d]-isoxazoles (323—326), indolo-[2,3-b]-l-pyrroline 1-oxides (327), 4//-1,2-benzoxazines (328), benzofuro-[2,3-c]-tetrahydropyrans (329), and monocyclic 1,2-oxazines (330). 

Diethyl (7,8-difluoro-3-methyl-3,4-dihydro-2//-benzoxazin-4-yl)methy-lenemalonate was cyclized in boiling acetic anhydride on the action of boron trifluoride in THF to give a pyrido[l,2,3-de]-l,4-benzoxazine-6-... 

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>. 

Diels-Alder reactions of 2-styryl-4//-l,3-benzoxazin-4-ones and maleic anhydride at 140°C gave 7-aryl-7,8,9,ll-tetrahydropyrido[2,l-b][l,3]ben-zoxazin-ll-ones[91IJC(B)754], but in boiling xylene 7-o-bromophenyl-l 1 -oxo-7,8,9,ll-tetrahydropyrido[2,l-h][l,3]benzoxazine-8,9-dicarboxylic acid was obtained from 2-(2-o-bromophenylvinyl)-4//-l,3-benzoxazin-4-one (96MI2). 

A highly unusual yet simple ring closure of 2-arylnitroethanes to 4/f-l,2-benzoxazines is accomphshed hy heating with TfOH. ... 

The heterocyclic ring of 3,4-dihydro-2//-l,3-benzoxazines (35) can adopt several half-chair conformations (see Figure 3). For 4-methyl derivatives (35 R = H, = Me) there is little difference between the energies of the isomers in which the C-4 methyl group is a- or jS-orientated, and the compound exists as a 54 46 mixture of 4-eq and 4-ax forms. However, when present, an A-alkyl group occupies a pseudoaxial position and this alters the balance. Thus, 3,4-dihydro-3,4-dimethyl-2//-benzoxazine (35 R = R = Me) is an 8 92 mixture of the 4-eq and 4-ax isomers <88JCS(P2)46i>. 

Treatment of 3-hydroxy-l,2-benzisoxazole with benzyl bromide gave a mixture of O-and iV-benzyl compounds. The iV-benzyl compound gave a benzoxazin-4-one on reaction with base, via the intermediates shown in Scheme 88 (78CPB549). 

Treatment of 7V-benzyl-l,2-benzisoxazolin-3-one with base produced a benzoxazine-4-one (see Scheme 88). The base catalyzed rearrangement of the 2-methyl-3-phenyl-l,2-benzoisoxolium salt to an oxazine is believed to proceed via a similar intermediate (67AHC(8)277). A number of other decompositions could possibly proced via this proposed route (74HCA376, 67AHC(8)277), which has also been postulated for the rearrangement of a variety of isoxazolium salts, e.g. the conversion of (200) into (202) (Section 4.16.3.3.2(i)(b)). 

Four-membered heterocycles are easily formed via [2-I-2] cycloaddition reac tions [65] These cycloaddmon reactions normally represent multistep processes with dipolar or biradical intermediates The fact that heterocumulenes, like isocyanates, react with electron-deficient C=X systems is well-known [116] Via this route, (1 lactones are formed on addition of ketene derivatives to hexafluoroacetone [117, 118] The presence of a trifluoromethyl group adjacent to the C=N bond in quinoxalines, 1,4-benzoxazin-2-ones, l,2,4-triazm-5-ones, and l,2,4-tnazin-3,5-diones accelerates [2-I-2] photocycloaddition processes with ketenes and allenes [106] to yield the corresponding azetidine derivatives Starting from olefins, fluonnaied oxetanes are formed thermally and photochemically [119, 120] The reaction of 5//-l,2-azaphospholes with fluonnated ketones leads to [2-i-2j cycloadducts [121] (equation 27)... 

Reaetion of l,3-benzoxazin-4-ones (43, 44) or trithioisatoie anhydride (45) with amidrazones (46, 47) or thiosemiearbazide (48) resulted in the formation of 3-(l-amidino)- (49-51) and 3-(l-thioureido)pyrimidines (52) respeetively. Compounds 49-52 underwent thermal intramoleeular ey-elization to the eorresponding l,2,4-triazolo[l,5-c]quinazolines (53-56) [68CB2106 76MI1 80PHA582 83MI1 85H(23)2357] (Seheme 18). 

Chiral 2,2-disubstituted l,3-benzoxazin-4-ones as auxiliaries in the synthesis of carbapenem antibiotics 97YGK858. 

A similar reaction pathway is even described for an aliphatic nitro group nucleophilic displacement. Nitrohydrazones 126 with sodium hydride provide acceptable yields (40-60%) of tricyclic [l,2,4]triazolo[5,l-c][l,4]benzoxazines 128... 

Depending upon the structure of the substrates 49, 52, and 56 hexahydropyrido[l,2-n]-[3,l]benzoxazines 50, 54, 2-aminobenzaldehyde 53, 1-substituted piperidones 51, 55, 57, 3,4,5,6-tetrahydropyridinium salt 58, or their mixture was obtained during the oxidation of 1-(2-hydroxymethyl-, 2-formyl- and 2-acetylphenyl)piperazines (49, 52, 56) with Hg(II)-EDTA complex (Schemes 6-8) (79AP219, 98ZN(B)37, 98ZN(B)1369). 

Cycloaddition of 2-styryl-4/7-3,l-benzoxazines and malononitrile gave 1 -amino-3-aryl-2-cyano-1 //,6//-pyrido[l, 2-n][3, l]benzoxazin-4-ones (99ZN(B)923). These tricyclic derivatives were also prepared in the reaction of 2-methyl-4//-3,l-benzoxazin-4-one and arylidenemalononitrile in AcOH in the presence of NaOAc. 

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