Heterocycles benzoxazines, from

Synthesis of fused heterocycles derived from 2H to 1,4-benzoxazin-3(4H)-ones 13HC387. 

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)... 

Benzoxazines are heterocyclic compounds obtained from reaction of phenols, primary amines, and formaldehyde.98,99 As described previously, they are key reaction intermediates in the HMTA-novolac cure reaction.40,43 Crosslinking benzoxazine monomers at high temperatures gives rise to void-free networks with high Tgs, excellent heat resistance, good flame retardance, and low smoke toxicity.100 As in HMTA-cured novolac networks, further structural rearrangement may occur at higher temperatures. 

Benzoxazine, an heterocycle present as structural subunit in many naturally occurring and synthetic bioactive compounds, was prepared under microwave irradiation from a mixture of 2-aminophenol 218 and an a-bromoester 219 (Scheme 80). The reaction proceeded through an initial base-catalyzed alkylation of the phenoUc OH followed by spontaneous amidation. Yields from 44 to 78% were reported for 17 different benzoxazines 220 [ 141]. 

The heterocyclic moiety of the diendo- and diexo-iv ed 2-oxo- and 2-thioxooctahydro- and -l,4,4a,5,8,8a-hexahydro-5,8-methano-3,l- and -1,3-benzoxazines assumes the exo- or endo-hodA conformation, respectively (or a somewhat twisted-boat form, cf. 344), as concluded from the H and C NMR data, in agreement with findings reported earlier [85T5159 87JCS(P2)599 cf. 91JST(246)301],... 

Aqueous base causes hydrolytic ring opening, although the ease with which this is achieved varies from system to system. AH- 1,3-Benzothiazines are quite stable at room temperature to aqueous alkali, but on heating the heterocyclic ring is destroyed by initial nucleophilic attack at C-2 (Scheme 9) (68ACH(58)179). 2H- 1,3-Benzoxazines are easier to hydrolyze and here both O-alkyl and imine bonds are cleaved by the action of water (Scheme 10) (3UA644). 

Iminodithiazoles 108 prepared from Appel salt 20 and o-aminobenzyl- and o-aminophenethyl-alcohols can be converted into 3,1-benzoxazine 109a and 3,1-benzoxazepine 109b by treatment with sodium hydride in THF (Equation 22) <1997SL704>. The oxygen-containing heterocycles 109 are apparently formed by cyclization of the alkoxide from dithiazole 108 onto the imine bond, followed by loss of S2 with generation of the cyano group. 

Hartenstein, H., Klein, J. and Sicker, D. 1993. Efficient isolation procedure for (2R)-2-P-D-Glucopyranosyloxy-4-hydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one from maize. Ind. J. Heterocycl. Chem. 2, 151-153... 

By electrolysis of 2-bromoamides in DMF the aminal esters (492 Scheme 89) are accessible. In the reaction of benzoylphenyl ketene with the isoquinolinedione (493) the heterocyclic aminal ester (494) is formed. Another heterocyclic aminal ester (496) was obtained from a hydrazinoyl chloride and a benzoxazine derivative (495). ... 

Aminophenols are valuable precursors of heterocycles. For example a benzoxazole has been obtained from an N-acyl, 2-aminophenol derivative in the following way. 2-Hydroxymaleanilic acid refluxed with triethylamine in methanol for 3 hours afforded a nearly quantitative yield of methyl [3,4-dihydro-1,4-benzoxazin-3(2H)-one-2-yl acetate (ref. 110). 

Different di-, tri-, tetra-, and pentacyclic heterocycles were prepared from 6,7-dihydro-l//,3//,5//-pyrido[3,2,l-y][3,l]benzoxazine (102) as depicted in Scheme 14 (78JHC645 79JHC829 80JHC1785 83EUP59698 84MIP1). See further examples in Section IV,B,6. 

In amidines transamination is possible,especially useful for such purposes are imidoylimid-azolides, e.g, (341 equation 172). In some cases it is useful to prepare amidines by ring opening of suitable heterocycles, which can be achieved by treatment with amines or other nucleophilic (baisic) compounds. Examples are the synthesis of amidines from 1,3,5-oxadiazinium salts (342), 3-amino-1,2-benzisothiazoles (343), 2-ethoxycarbonyl-3,l-benzoxazin-4(4//)-one (344), 1,2,5-oxa-diazolo[3,4]pyrimidine 1-oxides (pyrimidofuroxans 345) and l,2,4,6-thiatriazenium-5-olate 1,1-dioxides (346) as shown in Scheme 58. 

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. 

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