3- Aryl-2//-1.4-benzoxazines

Similarly, 3-oxo-6-nitrobenzoxazine, which is also a lactam, has been N-arylated using sodium hydride and 4-nitrochlorobenzene in dimethylformamide (DMF) <1985IJB1263>. The reaction is a nucleophilic aromatic substitution assisted by the 4-nitro group and is therefore not general to all aryl halides. However, there is a route to N-arylated benzoxazines 148-151 through a catalyzed tandem cyclization-arylation reaction of 147, shown in Scheme 9 <2004S2527>. 

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. 

Reaction of 2,3-dihydro-3-hydroxy-3-methyl- 240 (R = Me), or a mixture of 2,3-dihydro-3-hydroxy-3-aryl-57/-pyrido[l,2,3-dfe]-l,4-benzoxazin-5-ones 240 (R = Ar) and (8-aroylmethoxy)quinolin-2(l//)-ones 241 (R = Ar) with ethyl 2-(bromomethyl)acrylate in the presence of activated Zn and hydroquinone gave 8-[(2,3,4,5-tetrahydro-4-methylidene-5-oxo-2-furanyl)-methoxy]quinolin-2(l//)-ones (242) (97HCA1161). 6,7-Dihydro derivatives of 240 reacted similarly (00HCA349). 

The respective amide was prepared from 7-substituted 5-oxo-2,3-dihydro-5//-pyrido[l,2,3-de]-l,4-benzoxazine-6-carboxylic acids via acid chlorides with different benzylamines (00M1P3). 6-Carboxamides were N-benzylated, and a side-chain phenolic hydroxy group was O-alkylated. 7-Aryl-5-oxo-2,3-dihydro-5//-pyrido[l, 2,3-r/e]-1,4-benzoxazine-6-carboxylic acid was obtained from the ethyl ester by alkalic hydrolysis. 

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). 

Tandem mass spectrometry has been used to demonstrate that M+ as well as MH+ of substituted A-(ort/zo-cyclopropylphenyl)benzamides isomerizes before the fragmentation, with formation of 3-aryl-1-ethyl-lH-benzoxazines and 5-ethyl-2-oxodi-benzoazepines (Scheme 5.14). The methyl group in /V-[ortho-( 1 -methylcvclopropyl )-phenyl]benzamides quenches the latter process, leaving the formation of benzoxazines as the only cyclization reaction. A subsequent chemical experiment in solution confirmed the mass spectral predictions [24]. A similar study confirmed the analogy of cyclization of substituted A-(ort/zo-cyclopropylphenyl)-A -aryl ureas and N- ortho-cyclopropylphenyl)-A -aiyl thioureas in the ion source of mass a spectrometer and in solution [25]. 

Finally, the synthesis of 4//-3,l-benzoxazines 239 via a tandem aza-Wittig reaction (Scheme 89) should be mentioned. Carbodiimide 238 or isocyanate generated by an intramolecular aza-Wittig reaction bears an o-hydroxymethyl group on the A(-aryl substituent this OH attacks the carbodiimide C intramolecularly with cyclization to give a 3,1-benzoxazine (91S21). 

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 NMR chemical shifts of the C=N carbon in the open tautomeric forms of 2-aryl-substituted 3,4-dihydro-277-1,3-benzoxazines 5 and l,4-dihydro-277-3,l-benzoxazines 6 exhibited a reverse dependence on the benzylidenic substituents X. Electron-withdrawing substituents caused shielding (the shift was reduced), while electron-donating ones caused deshielding <2003JOC2151>. 

As a further interesting extension of the ring-chain tautomeric concept, 2-aryl-l,4-dihydro-2/f-3,l-benzoxazines encapsulated in a cage macromolecule exhibited different tautomeric ratios inside the cavity than those measured in deuterated mesitylene solution <2006JA9308>. 

The electronic effect of the substituent X on the 2-phenyl ring proved to influence the ring-chain tautomeric equilibria of 2-aryl-l-hydroxy-l,4-dihydro-2//-3,l-benzoxazines 79. While the proportion of the cyclic tautomer B in CDCI3 was 90% for the unsubstituted (X = H) and 70% for the />-methoxy derivative (X = OMe), no cyclic form could be detected in the case of the -dimethylamino compound (X = NMc2). Independently of the substituent X, the tautomeric equilibria of the regioisomeric 2-aryl-3-hydroxy-3,4-dihydro-2//-l,3-benzoxazines likewise contained no detectable amounts of the cyclic forms <1997CJC1830, 1998CJC389>. 

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>. 

The reactive zwitterions arising from the nucleophilic attack of imines 479 on the benzyne generated in situ from 2-(trimethylsilyl)phenyl triflate 478 proved to be an appropriate molecular scaffold for the capture of CO2 with sufficient electrophilicity to yield 2-aryl-3,l-benzoxazin+-ones 480 (Equation 53). Both substituents of the C=N bond affected the course of the reaction considerably the best yields were achieved by using imines with electron-rich or neutral aryl groups on the carbon, and benzyl or nonbranched chain alkyl substituents on the nitrogen atom. With substituted derivatives of 478, the unsymmetrically substituted arynes led to regioisomeric products <2006JA9308>. 

Cyclocarbonylation of o-iodophenols 503 with isocyanates or carbodiimides and carbon monoxide in the presence of a catalytic amount of a palladium catalyst (tris(dibenzylideneacetone)dipalladium(O) Pd2(DBA)3) and l,4-bis(di-phenylphosphino)butane (dppb) resulted in formation of l,3-benzoxazine-2,4-diones 504 or 2-imino-l,3-benzoxazin-4-ones 505 (Scheme 94). The product yields were dependent on the nature of the substrate, the catalyst, the solvent, the base, and the phosphine ligand. The reactions of o-iodophenols with unsymmetrical carbodiimides bearing an alkyl and an aryl substituent afforded 2-alkylimino-3-aryl-l,3-benzoxazin-4-ones 505 in a completely regioselective manner <1999JOC9194>. On the palladium-catalyzed cyclocarbonylation of o-iodoanilines with acyl chlorides and carbon monoxide, 2-substituted-4f/-3,l-benzoxazin-4-ones were obtained <19990L1619>. 

While this chapter was being edited and revised, new data appeared on the chemistry of 1,3-oxazine derivatives. In a recent review on the applications of 1,3-amino alcohols in asymmetric organic syntheses, the use of numerous 1,3-oxazine derivatives for this purpose was discussed <2007CRV767>. A compilation on the progesterone receptor ligands provides a brief summary of the progesterone receptor modulatory effects of 6-aryl-l,4-dihydro-3,l-benzoxazin-2-ones <2007MI374>. 

The 6//-l,3-thiazin-6-iminium hydroperchlorate salts 78-81 give interesting products when treated with nucleophiles <2003H(60)2273>. Hydrolysis of 6-imino-6//-l,3-thiazine hydroperchlorate 78 affords (2Z,4Z)-2-cyano-5-hydroxy-5-phenyM-azapenta-2,4-dienethioamide 82 in excellent yield, while treatment with morpholine gives 2-(morpholinomethylene)malononitrile 83 and thiobenzamide. The 5-(ethoxycarbonyl) -(methylthio)-2-aryl-6/7-l,3-thiazin-6-iminium salts 79 and 80 react with hydroxide or morpholine to afford ethyl 4-(methylthio)-2-aryl-6-thioxo-l,6-dihydropyrimidine-5-carboxylates 84 and 85. In the case of the 4-chloro analogue 80, the (Z)-ethyl 2-(5-(4-chlorophenyl)-37/-l,2,4-dithiazol-3-ylidene)-2-cyanoacetate 87 is also formed for the reaction with sodium hydroxide. The 1,2,4-dithiazoles 86 and 87 can be obtained as the sole product when 79 and 80 are treated with sodium acetate in DMSO. Benzoxazine 88 is isolated when the iminium salt 81 is treated with morpholine or triethylamine. Nitrile 89 is formed as a ( /Z)-mixture when 6-imino-67/-l,3-thiazine hydroperchlorate 79 is reacted with triethylamine and iodomethane in methanol <2003H(60)2273>. 

Indolones (158 R = aryl) or their water adducts (175 R = aryl, alkyl Nu = OH) are oxidized by peracids, under mild conditions, to benzoxazines (142 R = aryl, alkyl). The reaction is a general one. The reaction may proceed by the intermediate oxirane (120) or by initial addition of the peracid across the azomethine linkage (202).48 Oxidation by aqueous permanganate or dichromate gives iV-acylanthranilic acids (203 R = aryl, alkyl).48"50... 

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). 

Benzoxazin-4-ones (39) react with amines to give quinazolinones (40) (77JOC656), but this typical reaction is replaced in 1,3-benzoxazine-2-thiones (41) by the formation of imino derivatives (42) since now the oxygen ring atom is joined directly to the aryl nucleus (76MI22700). 

Dihydro-2//-1,3-oxazines and -benzoxazines are stable to cold aqueous alkali, but hot dilute acids effect ring scission. In the monocyclic series the products are the salts of 3-aminopropyl esters (71) which rearrange to 3-hydroxypropylamides on basification. Should there be an aryl group at position 6 in the starting material, rearrangement is often followed by dehydration to styrene derivatives (72 Scheme 24) (72AG(E)287). 

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). 

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). 

Nitroalkenes react with benzene derivatives at low temperature in triflic acid to afford a-aryl ketones after quenching with methanol182,183 [Eq. (5.74)]. At higher temperature the 0-protonated oxime intermediate may react further to yield 4//-1,2-benzoxazines (see Section 5.14.1.3). a-Nitrocarbonyl compounds show similar characteristics as alkylating agents to yield oximes with the involvement of the tricationic intermediate 44.181... 

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