Benzoxazine system

There are two types of benzo derivatives differently annulated namely, benzo-4//-l,3-oxazinium 42 and benzo-4//-3,l-oxazinium salts 46. Some information about uncharged benzoxazine systems has been summarized in a review [62HC(17)341]. The chemistry of the corresponding salts has been almost unknown. 

Potassium organophosphide reagents also continue to find applications in synthesis. Direct displacement of fluoride from fluoroaromatic substrates by potassium diphenylphosphide is the key step in the synthesis of the phosphi-noarylsulfoxides (88), water-soluble phosphino-amino acid systems, e.g. (89), ° and the chiral benzoxazine system (90). Related displacement of fluoride by potassium monophenylphosphide has been used to prepare a series of hydrophilic triarylphosphines, e.g. (91). Among new phosphines prepared by conventional displacement reactions by potassium diphenylphosphide on... 

The only known representative of the pyrimido[2,l-Z>][l,3]benzoxazine system, (285), was formed from S-methyl-2-thiouracil (284) and 2-acetoxybenzyl bromide in a one-pot reaction (Equation (79)) <87JCR(M)1286>. 

We tried to improve the donor-acceptor properties obtained for previously reported compounds [26,162] by combining a strong electron-acceptor moiety such as benzo-TCNQ or benzo-DCNQI with the 1,4-benzoxazine system as the donor fragment. The synthesis of compounds 92 and 94 was carried out according to Scheme 1.17 by reaction of 2,3-dichloro-1,4-naphthoquinone with 2-methylaminophenol in pyridine yr) at 100°C to yield the novel A(-methylben-zo[6]phenoxazin-6,11-dione (91) in good yield. 

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)... 

Lim et al. also investigated HMTA-phenolic reactions with somewhat larger model compounds (e.g., two- and four-ring compounds) and established that similar reaction pathways to those described previously occurred.50 For these model compounds (as opposed to one-ring model compounds), which are more representative of typical oligomeric systems, increased molecular weight favored die formation of hydroxybenzylamines but not benzoxazines. This was suggested to be a steric effect. 

The key intermediate for the antibacterial agent levofloxcin, (,S>( )-7,8-difluoro-2,3-dihydro-3-methyl-4H-l,4-benzoxazin, was prepared by the asymmetric hydrogenation of (442) by the catalyst system made in situ from [Ir(cod)Cl]2, biphosphine and bismuth(III) iodide.703 The product was isolated in 96% yield, with an enantiomeric purity of 90% for the biphosphine (2S,45)-BPPM,(2S,45)-N-( -butoxy-carbonyl)-4-(diphcnylphosphino)-2-[(diphcnylphosphino)mcthyl]-pyrrolidine. 

Readily available copper(II) complexes derived from o-nitrosophenols react with dimethyl acetylenedicarbonxylate to give the 1,4-benzoxazine products that would be expected from formal [4 + 2] cycloaddition across the diheterodiene system (Scheme 168).239 No such reaction is observed in blank experiments with uncomplexed tautomeric nitrosophenols hence the copper may cause sufficient electronic perturbation within the heterodiene complex to allow reaction to occur. 

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). 

The ring closure of N- 1,4-benzoxazin-6-yl)aminomethylenemalonates (80) in boiling diphenyl ether for 30 min gave mixtures of isomeric 1,4-oxazino[2,3-g]quinoline-8-carboxylates (865) and l,4-oxazino[3,2-/]quin-oline-6-carboxylates (866) in good yields, with an excess of the linearly anelated ring systems (865) [88IJC(B)649]. 

In the discussions, the syntheses, stereochemistry, and transformations of cycloalkane d -fused and e -fused systems are described in parallel these correspond to 3,1-benzoxazines and 3,1-benzothiazines, and to 1,3-benzoxazines and 1,3-benzothiazines, respectively. The syntheses are frequently similar, but totally different methods are often used for the d -fused and e -fused heterocycles. The main syntheses (A-J) of the ring systems discussed in this review are given in Fig. 1. 

To increase the yields of the ring closure reactions, a new method was developed that was successfully applied for the synthesis of alicyclic fused systems of both the parent oxazolidine-2-thione and tetrahydro-1,3-oxazine-2-thione (85S1149). As an example, the synthesis of 2-thioxoperhydro-l,3-benzoxazine 103 is described. The dithiocarbamate 101, prepared from the amino alcohol 100, carbon disulfide and triethylamine, was treated with ethyl chloroformate in the presence of triethylamine, to give the thioxo derivative 103 via the transition state 102 (85S1149). In this way, the fused-skeleton thioxooxazines (91, X = S, 92) can be prepared with considerably higher yields (50-70%) than by the earlier methods (85S1149). 

The linear regression analysis data are listed in Table VIII. For ease of comparison, the data on the parent 2-aryltetrahydro-l,3-oxazine 389 and the corresponding 1,3- and 3,1-benzoxazine isomers 392 and 397 are also given. The data in Table VIII show that p is practically the same for all the 1,3-oxazine ring systems investigated, whereas the intercept values are characteristic of the substituents. 

Several substituted hydroxy amines have been treated with acetylenic esters to give different heterocyclic systems. Thus, the reaction of o-aminophenol with diethyl acetylenedicarboxylate gives 3-carbethoxy-methylene-3,4-dihydro-2i/-l,4-benzoxazin-2-one (24) [Eq. (8)]. In... 

C-O, N-O, and N-C bonds, and this induces additional strain in the oxazine system 7 <2000EJ02613>. Extrusion of formaldehyde from iV-acetyl-2,1-benzoxazine 8 to give imine 9 involves a concerted breaking of both the C-C and N-O bonds <1996J(P2)1367>. The experimental barriers are lower than the theoretical one predicted by AMI for the decomposition of 8 in the gas phase. 

Starting from o-ethynylphenyl-urea derivatives the quinoline, quinazoline and benzoxazine ring systems could be prepared selectively (4.25.). The opening step of the process in each case is the desilylation of the acetylene, which is followed by the palladium(II) catalyzed attack of the nitrogen or... 

The reported examples of this ring system were obtained by the reaction of 2-ureidobenzonitrile (89JPR537) or 2-alky 1-4H--3, l-benzoxazin-4-one (84CPB2160) with anthranilic acid nitrile to give 6-aIkyI-13//-quinazolino[3,4-a]quinazolin-13-ones (546). 

However, Aae can still be used in suitable cases as an indication of conformation, particularly for polycyclic compounds. Thus Aae measurements on TV-CH2X protons may be used to establish the cis or trans nature of the ring fusion in 1,3-heterocyclic systems. For example, the trans-fused perhydro-pyrido[3,2,l-iJ][3,l]benzoxazine (21) shows Aae 0.84 ppm, indicative of the anti-coplanar CH-nitrogen lone-pair geometry, whereas the cis-fused isomer (22), in which the nitrogen lone pair bisects the CH2 group, shows Aae 0.12 ppm.45... 

The conformations of tri- and tetracyclic compounds containing the per-hydropyrido[l,2-c][l,3]oxazine system have been determined by H-NMR spectroscopy. The four perhydropyrido[3,2,l-i/][3,l]benzoxazines 269, 270, 280, and 281 have been isolated, and the O-outside cis-conformational analog of 266, which has not been observed in the bicyclic series, was shown to possess the same Jtem (—7.5 Hz) for the NCH20 protons as that of the... 

Benzoxazines and 1,2-benzothiazines are rarely encountered except as carbonyl derivatives or as 5-oxides respectively. However, an interesting representation of the 2,1-benzothiazine system is provided by the zwitterion (9) which is formed by successive treatment of the 2-aminostyrene (8) with iV-chlorosuccinimide and potassium hydroxide (see Section 2.27.3.1.1. ii). On protonation it gives the salt (10). 

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). 

Such compounds are unstable unless the double bond is held in conjugation with other systems as, for example, when it is part of an aryl ring. Indeed, dihydro-3,1-benzoxazines are readily accessible from 2-aminobenzyl alcohols by condensation with aldehydes or ketones (Scheme 84) (75AP622). Oxacephems (199) also contain the 3,6-dihydro-2//-l,3-oxazine unit and they are formed for instance, on cyclization of chlorolactams (198) by the action of stannic chloride (B-80MI22701). 

The first representative 57 of pyrido[2,l-/]-3,l-benzoxazine ring system was synthesized by the ring-closing methathesis of perhydro-3,l-benzox-azine 113 in the presence of the second generation of Grubb s catalyst (06TL3815). 

To 2.0 ml of Amberlite XAD 7 was added 2.0 ml of a 0.05 M phosphoric acid buffer (pH 7.0) having dissolved therein 20 mg of lipoprotein lipase, and the system was allowed to stand at room temperature for 18 hours to thereby adsorb the enzyme onto the resin. The resin was filtered. A solution of 250 mg of 3,5-dinitrobenzoyl derivative of ()-3-acetoxymethyl-7,8-difluoro-2,3-dihydro-4H-[l,4]benzoxazine as a substrate in 25 ml of a mixed solvent of benzene and n-hexane (4 1 by volume) was added to the resin, followed by... 

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