Benzoxazine, alkylative cyclization

Gallagher et al. reported on various IV-heterocycle construction via cyclic sulfamides. Using this strategy, they synthesized enantiopure 1,4-benzoxazine 311, which was the precursor of the blockbuster antibiotic levolloxacin 312 (Scheme 40.67). Starting from Boc-protected amino alcohol 305, sulfamidate 306 was prepared using RuCU and NaI04. 306 was treated with halo phenol 308 followed by acidic hydrolysis to afford amino ether 310. The compound 310 underwent Pd-catalyzed C—N alkylative cyclization to produce benzoxazine 311, which was the potential precursor from which Levolloxacin 312 can be synthesized. 

The second-resolution approach relied on enzymatic resolution of acetate esters 62 (Scheme 4.7) (Hayakawa et ah, 1991). The sequence opened with the alkylation of 2,3-difluoro-6-nitrophenol (59) with l-acetoxychloro-2-propane (60) to deliver ether 61. Reduction of the nitro group of 61 gave an intermediate anihne that cyclized to give racemic benzoxazine 62 in 62% yield. A variety of lipases were then examined for the resolution. The best results arose from use of LPL Amano 3, derived from P. aeruginosa, which gave a ratio of 73 23 in favor of the desired (—)-enantiomer. Benzoylation of the enantiomerically-enriched mixture followed by chromatography of the aryl amides delivered enantiomerically pure 63. 

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>. 

Hydroxychalcones (202) react with either alkyl or aryl isocyanates to give 3,4-dihydro-4-phenacyl-l,3-benzoxazin-2-ones (203). Carbamates form initially and these require heating in the presence of potassium hydroxide in order to effect cyclization to the benzoxazinones (Scheme 56). By heating a mixture of all of the reactants at once the preparation can be run as a one-pot reaction <88S246>. 

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>. 

The methods most frequently used to synthesize these compounds are [6 + 0(a)] cyclizations. Ring closures may take place via intramolecular alkylation, condensation, or nucleophilic substitution. The starting materials for the cyclizations in the case of pyrazino-oxazines are always pyrazine derivatives. Only a few representatives of these systems have been prepared. Pyrimido-oxazines are the most explored group of compounds. In the bicyclic series, cyclizations have been carried out in most cases from pyrimidine intermediates and only rarely from morpholino intermediates. For the preparation of benzo-fused derivatives, both benzoxazine and quinazoline intermediates have been used. Pyrazino-oxazines represent a small group of compounds. For cyclizations, both pyrazino and oxazino intermediates have been used. There are many lactone structures among these compounds. For their preparation, the usual methods of lactone formation have been applied. 

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