Benzoxazines, preparations

Poly(phenylquinoxaline—arnide—imides) are thermally stable up to 430°C and are soluble in polar organic solvents (17). Transparent films of these materials exhibit electrical insulating properties. Quinoxaline—imide copolymer films prepared by polycondensation of 6,6 -meth5lene bis(2-methyl-3,l-benzoxazine-4-one) and 3,3, 4,4 -benzophenone tetracarboxyUc dianhydride and 4,4 -oxydianiline exhibit good chemical etching properties (18). The polymers are soluble, but stable only up to 200—300°C. 

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. 

Chiral 3-alkylpiperidines were prepared through perhydropyrido[2,I-Z)][],3]benzoxazines (99TL242I, 00TA2809). 5u-Pentyl-5u,6,7,8,9,H-hexa-hydropyrido[2,I-Z ][l,3]benzoxazin-9-ones 31, 33 (R CsHn) and 34 were used in the total synthesis of racemic and natural (—)-(R) forms of adalinine alkaloid (99SL37, 99TL739). 

A side-chain COOH group in 5//-pyrido[l,2,3- 7e]-l,4-benzoxazin-5-one was reduced into a HOCH2 group with NaBH4 in a 1 1 mixture of MeOH and THE at 5°C (98MIP13). Ethyl 7-oxo-2,3,6,7-tetrahydro-5//-pyr-ido[l,2,3- 7e]-l,4-benzoxazine-2-carboxylate was prepared by the catalytic hydrogenation of the l-oxo-5H derivative over 10% Pd/C catalysts in EtOH (99EUP894796). 

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. 

Ox 0-2,3-dihydro-7//-pyrido[l, 2, i-de]-1,4-benzoxazine-6-carboxylic acids were prepared from 6-esters under acidic (96JAP(K)96/291144, 98MIP19, 98MI37, 99H(51)1563, 99MI36, 00MI76) and under alkalic conditions (OOMIPIO). 

Oxo-2,3,6,7-tetrahydro-5//-pyrido[l,2,3- /e]-l,4-benzoxazine-2-carbox-ylates (291, X = H2) were obtained by hydrogenation of 4-substituted 3, 4-dihydro-2//-1,4-benzoxazine-2-carboxylates (290, X = H2) over 10% Pd/C catalyst, then by the treatment of free acids with (CF3C0)20 (99EUP894796). 5,7-Dioxo-2,3,6,7-tetrahydro derivatives 291 (X = 0) were prepared similarly from 290 (X = O). The products 291 (X = O) exist in 7-hydroxy-5-oxo-2,3-dihydro-5// tautomeric form. 

R = H, R =Br, R" =Et) was prepared by cyclization of aroylacetate 314 (R = H, R =Br, r2 = H, X = F) (OOMIPIO). 9,10-Difluoro-3(5)-methyl-7-oxo-7//-pyrido[l,2,3- /e]-l,4-benzoxazine-6-carboxylic acid and its racemic form were prepared in the reaction of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-2-ethoxymethyleneacetate and (R)- or (i ,5)-2-aminopropanol and subsequent hydrolysis of the ring closed tricyclic esters (98MI45). Cyclization of ethyl 2-(2,3-difluoro-5-iodobenzoyl)-2-[A-(2-hydroxyethyl)aminomethylene]acetate 315 in the presence of K2CO3 in DMF at 95 °C for 3.5 h yielded 9-iodo-7-oxo-2,3-dihydro-7//-pyrido[l,2,3- /e]-l,4-benzoxazine-6-carboxylate (01MIP2). 

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]. 

Very little is known about the parent benzoxazine analogue,1 due to difficulties in the preparation of o-nitrosophenol. Synthetic procedures and practical application of spironaphthooxazines can be found in the patent literature and have been reviewed.72... 

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. 

Oxopyrido[l,2,3- ( ]-l,4-benzoxazine-6-carboxylates 377 could be prepared from l-(2-hydroxyethyl)-4-oxo-l,4-dihydroquinoline-3-carboxylates 376 by treatment with a base (NaH, KOH, KF, K2C03, or Bu OK) (Equation 67) <1996WO96/004247, 1997H(45)137>. The 0-acetate of 376 <1997H(45)137> could be similarly cyclized. Ofloxacin... 

The l,2,3,4,4 ,5-hcxahydro-pyrazino[2,l-t ][l,4]benzoxazinc 350 was prepared from the appropriately substituted benzoxazine 349, as shown in Scheme 56 <1997BML763, 2003JME2877>. Diethyl oxalate <2001USP6169086> and dibromoethane <2002W02002/020533> were also utilized to build the pyrazino ring of [l,4]oxazino[4,3-tf]quinoxalines. 

Arylbenzoxazoles have been prepared in moderate yields by allowing aromatic aldehydes to react with copper complexes of o-nitrosophenols (Scheme 108).172 The role of the copper in reactions of this type is unclear but it may be noted that the uncomplexed nitrosophenols are relatively labile.173 Copper complexes of o-nitrosophenols have also been used for the synthesis of benzoxazines (see Section V,D). 

Thermolysis of the hydrazone 497 having an azido group, prepared from the respective chloro derivative 496, in boiling benzene gave 3,4,4a,5-tetrahydro[l,2,4]triazino[6,l-c][l,4]benzoxazines 498 [80TL559 82JCS-(Pl)755], whose X-ray structure was studied [83AX(C)605]. The reaction... 

N-( 1,4-Benzoxazin-6- and -7-yl)aminomethylenemalonates (80 and 82) were prepared in 76-91% yields when 6- and 7-amino-1,4-benzoxazines (79 and 80) were reacted with EMME by heating on a steam-bath for 2 hr [88IJC(B)649J. 

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