Cyclization benzoxazine-2-ones from

The effects of stereochemistry, substitution, and (for 2-phenylimino derivatives) an intramolecular cyclization of the ions [M-H] have been observed in the electron ionization mass spectra of as- and /ra r-fused 4-phenyloctahy-dro-2//-3,l-benzoxazin-2-ones 21 and -2-thiones 22, 2,4-diphenylhexahydro-3,l-benzoxazines 23, and 2-phenyl-imino-4-phenylhexahydro-3,l-benzoxazines 24. The mass spectral behavior was similar for the isomeric compounds, although they could usually be differentiated from each other on the basis of the relative abundances of their characteristic fragment ions <2005ARK(iv)39>. 

Reformatsky reactions of Af-(2-bromoalkanoyl)-l,3-benzoxazin-4-ones 267 and 272 and imines derived from aniline or /)-substituted anilines gave fra j -/3-lactams 273 with complete diastereoselectivity, and the l,3-benzoxazin-4-one auxiliary 269 could also be recycled. However, in the similar transformations of imines containing an o-methoxyphenyl substituent on the nitrogen, no cyclization to azetidinone occurred and /r -/3-aminocarboxamide derivatives 274 were the only products formed (Scheme 51) <2005S725>. 

In the thermal cyclization of 3-alkoxyphenyl A -(l-aryl-2,2,2-trifluoroethylidene)carbamates 287, obtained from 3-alkoxyphenols 285 and l-aryl-l-chloro-2,2,2-trifluoroethyl isocyanates 286, 2-aryl-2-trifluoromethyl-2,3-dihydro-477-l,3-benzoxazin-4-ones 290 were formed instead of the regioisomeric l,3-benzoxazin-2-ones 288 (Scheme 53). The formation of 290 was explained by a thermal isomerization of 287 involving a skeletal 1,3-rearrangement of the electron-rich aryloxy group to the azomethine carbon, which is electron deficient due to the electron-withdrawing CF3 group <2002JFC(116)97>. 

The carbamates formed from 2-hydroxychalcones and alkyl or aryl isocyanates readily cyclize to 3,4-dihydro-l,3-benzoxazin-2-one derivatives <1996CHEC-II(6)301>. When hydroxychalcones 318 with a benzofuran moiety were heated under reflux with phenyl isocyanate in benzene in the presence of a catalytic amount of potassium hydroxide, l,3-benzoxazin-2-one derivatives 320 were formed through the intermediate open-chain carbamates 319 (Scheme 61) <2006JHC437>. 

Eormation and subsequent cyclization of a hydroxyalkyl carbamate bearing an activating O-substituent can also be achieved in a one-pot procedure. When 2-(hydroxymethyl)aniline 394 was treated with -nitrophenyl chloroformate, the formation of the /)-nitrophenylcarbamate intermediate 395 was followed by in situ ring closure to give the 3,1-benzoxazin-2-one derivative efavirenz 250 in high yield and with high purity, free from the intermediate 395 (Scheme 74) <1998JOC8536>. 

The thermally induced cyclization of A -(benzyloxycarbonyl)phenyl ketenimines 415, obtained in a two-step, one-pot procedure from benzyl 2-azidobenzoates 414, led to 2-substituted-4/f-3,l-benzoxazin-4-ones 416 (Scheme 79). The reaction involves the formation of a new carbon-oxygen bond and migration of the benzyl group from the oxygen atom to the terminal carbon atom of the ketenimine fragment <2005S2426>. 

Both phenylhydrazones and imines derived from 5-halogeno-2-hydroxyacetophenones 510 were cyclized to the corresponding 4-methylene-substituted l,3-benzoxazin-2-ones 194 and 511 on treatment with 0.5 or O.bequiv of triphosgene under mild conditions (Scheme 96) <2003X8163, 2004SC71>. In the similar reactions of arylhydra-zones of 2-hydroxyacetophenones with 1 equiv of triphosgene, spiro-l,3-benzoxazine dimers were formed <2002JCM473>. 

A more general approach, however, is the cyclization of the monooximes of a,0-unsaturated 1,4-dicarbonyl compounds. Thus, the monocyclic oxazine (121) is formed when the butenedione (120) is heated with hydroxylamine (50JOC869), and 2,3-benzoxazin-l-ones (123) are prepared similarly from the oximes of 2-acylbenzoic acids (122) (37LA(531)279). 3-Aryl-l,2-oxazin-6-ones are available through the action of hydroxylamine in acid solution on the trichloroketones (124 Scheme 49) (80ZC19). 

Alkoxy-l,2-dihydro-3,l-benzoxazin-4-ones are often prepared from anthranilic acids by reaction with alkyl chloroformates in the presence of pyridine <87PHA694>. More complex compounds such as the [3,l]benzoxazino[2,l-i][l,3]oxazin-5-ones (285) are synthesized through a tandem cycliz-ation process when A-(2-hydroxybenzyl)anthranilic acids (284 X = H, Me, or Cl Y = H, or Me) are treated with trifluoroacetic anhydride <88JHC297>. When reacted with acetic anhydride, however, the course of the reaction is changed and quino[2,l-i][l,3]benzoxazines (286) are produced (Scheme 83) <89JHC237>. 

When acid chlorides were used instead of cumulenes in the reaction with o-iodoanilines 3 and carbon monoxide (20atm), 2-substituted-4H-3,l-benzoxazin-4-ones 8 were obtained in good to excellent yields, also in the absence of a phosphine ligand [23]. The reaction is believed to proceed via in situ amide formation from o-iodoaniline and acid chloride, followed by oxidative addition to Pd(0), CO insertion, and intramolecular cyclization (Scheme 13.3). 

Labelling studies ( 0) on the thermal cyclization of o-benzamidobenzoic acid to 2-phenyl-3,l-benzoxazin-4-one (320 R = Ph) reveal that oxygen is lost with equal probability from the CO2H and COPh groups.3,l-Benzoxazin-4-ones (320 R = Me or Ph) are the products of a remarkable ring-expansion, sulphur-extrusion process undergone by 0-acyl-2,l-benzisothiazolones (321 R = Me or Ph) in hot pyridine solution (Scheme 76). ... 

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