1,4-Benzoxazines reduction

The group of Caliendo and coworkers has described a multistep synthesis of benzoxazine libraries, in the context of a search for compounds with vasorelaxant activity related to cromakalim [454]. As highlighted in Scheme 6.264, all of the required synthetic manipulations were carried out under microwave irradiation conditions. In all cases, a reduction in reaction time as compared to the corresponding thermal protocols was reported. 

Bobowsky and Shavel found an interesting intramolecular reductive transacylation reaction, in which substituted cyclopent[e][l,3]oxazin-2-ones and l,3-perhydrobenzoxazin-2-ones (90) were formed (80JHC277). In the reactions of 4-(2 -oxocycloalkyl)-3,4-dihydro-3-methyl-2//-l,3-benzoxazin-2-ones 88 and potassium borohydride, the 2 -hydroxycycloalkyl products 89 obtained underwent intramolecular transacylation reactions, resulting in the dihydro-1,3-oxazine derivatives 90. In this way, the 4-(2 -oxocycloalkyl)... 

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. 

A double reduction was achieved under catalytic hydrogenation conditions to open the epoxide and reduce the nitro group to an amino group in 90% yield. The aniline thus afforded was reacted with diethylethoxymethylenemalonate to give 92. 92 was next cyclized to the 1,4-benzoxazine 93 via a Mitsunobu reaction in the absence of a Lewis acid, unlike Kim s approach (Kang et al., 1996). Completion of the tricycle core was ultimately achieved in PPE at 140-145°C to furnish the LVX core in 85% yield. The core was converted to LVX (1) in two precedented steps. 

Reduction of cycloalkane-condensed 2-phenyl-5,6-dihydro-4//-l,3-benzoxazines 144 with lithium aluminium hydride (LAH) afforded A -benzyl-substituted 2-(aminomethyl)cycloalkanols 145 in a reductive ring opening via the ring-chain tautomeric tetrahydro-l,3-oxazine intermediates. Catalytic reduction of 1,3-oxazines 144 under mild conditions in the presence of palladium-on-carbon catalyst similarly resulted in formation of the A -benzyl-1,3-amino alcohols 145. When the catalytic reduction was performed at elevated temperature at hydrogen pressure of 7.1 MPa, the N-unsubstituted 2-(aminomethyl)cycloalkanols 146 were formed in good yields (Scheme 22) <1998SC2303>. 

In the reactions of the perhydro-l,3-benzoxazine derivatives 236 with benzeneselenyl chloride in dichloromethane-methanol, methoxyselenylation of the double hond in the C-2 side chain occurred in a highly regio- and diastereo-selective way (Scheme 43). Reductive deselenylation of 237 with triphenyltrn hydride in the presence of a catalytic amount of azobisisobutytonitrile (AIBN) resulted in formation of the methoxy derivatives 238 <2006JOC2424>. 

An electrochemical cyclization leading to both benzoxazines and dihydrobenzoxazines is shown later in this section (Scheme 34). Finally, oxazine 304 was formed in a reductive, dehydrative dimerization of 303 (Scheme 33) <1961CIL254>. 

The reduction of indolones is described together with the reduction of isatogens. The major products of reduction are indoxyls and diindoxyls. In some cases the indoxyls are oxidized by air to benzoxazines (Section III,B). Indolones are comparable with isatogens as oxidizing agents88... 

The reduction of oxaziridines, anthranils, and benzoxazines was discussed in Part I. 

The reduction of 2,3-benzoxazin-l-one with ring contraction to a phthal-imidine (Part I) has been used as a model for asymmetric induction by an alkaloid a low concentration (1.4 x 10-4 M) of strychnine induces some chirality during reduction in an acetate buffer (optical yield about 5%).269... 

H- 1,4-Benzoxazines (241) are available by the cyclization of acetals (240 X = 0) in acid solution (79M257). Similarly the reduction of 2-nitrophenoxyacetophenones (242) with zinc dust and ammonia affords the corresponding JV-oxide derivatives (243) (79T1771). 

Dihydro-l,4-benzoxazin-3-ones and -benzothiazin-3-ones are synthesized by the reductive cyclodehydration of 2-nitrophenoxyacetic acids or their thioxy equivalents and as these heterocycles have an active methylene group it is a simple matter to prepare 2-substituted derivatives by condensation reactions with aldehydes and other carbonyl compounds (Scheme 123) (79AP302). 

Reduction of 8-nitro-9,10-difluoro-7-oxo-2,3-dihydro-7H-pyrido[l,2, 3-cfe][l,4]benzoxazine-6-carboxamides with Na2S204 in aqueous MeOH under reflux for 5 h gave 8-amino derivatives in 51-74% yields (09WOP2009/035634). 8-Amino derivative was obtained from (S)-8-nitro-9-fluoro-10-(l-aminocyclopropyl)-7-oxo-2,3-dihydro-7/T-pyrido[l,2,3-de][l,4]benzoxazine-6-carboxylic acid by catalytic hydrogenation over Pd/C catalyst in AcOH (06MIP1). 

Another interesting reaction of benzoxazines 114 (115) is the reductive opening of the oxazine ring with simultaneous dehydrogenation of the pyrazoline moiety [170]. This process is carried out in a KOH suspension of a mixture of dimethyl sulfoxide and dimethylformamide. For instance, this treatment involving 2,5-diary l-l,10b-dihydro-177-pyrazolo[l,5-c]benzo[e]-l,3-oxazines 116 leads to the formation of pyrazoles 117 (Scheme 2.32). Similar disproportionation reactions have also been described for some bezopiranes, for example, pyrazole derivative 118 [91, 170]. 

A strategy for producing unsymmetrical TB derivatives is based on the Wilcox synthetic protocol (Scheme 5). The reaction of aniline 4 with the derivative of isatoic anhydride, 3,l-benzoxazine-2,4(l//)-dione 5, or 2-nitrobenzoic acid 6 affords ami-noamide 7 and nitroamide 8, respectively. The reduction of 7 or 8 followed by a final cyclization reaction of bisamine 9 yields unsymmetrical TB derivatives 10 (90JOC363). 

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