Oxazepine

Chamicel Name 2-Chloro-11-(1-piperazinyl)dibenz[b,f] [1,4] oxazepine... 

A mixture of 10 g of the above piperazine carboxylate ester, 8 g of phosphorus pentoxide and 20 ml of phosphorus oxychloride is heated under reflux for about 1 day, diluted with 100 ml each of chloroform and benzene and quenched with 200 g of ice. The mixture is made basic with 10% sodium hydroxide. Theorganic layer is Isolated and extracted with 150 ml of dilute hydrochloric acid. The product is precipitated from the aqueous layer by addition of 10% sodium hydroxide, extracted with benzene and dried over potassium carbonate. Recrystallization from benzene-petroleum ether gives 2[Pg.77]

This crude product is dissolved in 100 ml of dilute hydrochloric acid, the acid solution is extracted with ether, and the aqueous layer is made basic with sodium hydroxide solution (3N) in the presence of ether (approximately 250 ml). The ether layer Is separated, dried over potassium hydroxide and evaporated to a white solid. Additional purification by repeating the formation of the hydrochloric acid salt and reprecipitation of the base is carried out. When purified in this manner, followed by drying at 80°C in vacuo over phosphorus pentoxide, 2-chloro-11-(4-methyl-1-piperazinyl)dibenz[b,f] [1,4]oxazepine, li/IP 109° to 111°C, is obtained. 

The first fully unsaturated 1,4-oxazepines 3 were prepared by the photoisomerization of 3-oxa-6-azatricyclo[3.2.0.02,4]hept-6-enes l.29,30 The reaction proceeds via the bicyclic intermediates 2 which undergo valence isomerization. 

An ice-cold solution of a 3-oxa-6-azatricvclo[3.2.0.02,4]hept-6-ene 1 (0.5-1.0 mmol) in MeCN (200 mL) was irradiated with a 30-W low-pressure Hg lamp for 10-125 min. The solvent was removed under reduced pressure and the residue was treated with active charcoal and hexane/i-Pr20. The mixture was filtered and the filtrate was evaporated under reduced pressure to leave the almost pure 1,4-oxazepines as orange oils, which showed vmal (neat) — 1660-1650 cm-L The products decomposed on attempted chromatography. 

Dibenz[(j,/][1,4]oxazepines 2 are readily obtained by the cyclodehydration of 2-(acylamino)-phenyl phenyl ethers 1 in polyphosphoric acid.38... 

The diastereoselectivity and the stereochemical outcome of the addition of 2,3,4,6-tetrahydro-3, 4-dimethyl-2-phenyl-1,4-oxazepine-5,7-dione, derived from ephedrine and methyl hydrogen malonate, to 1 -nitrocyclohexene was found to be dependent on the nature of the base and the solvent. The highest diastereoselectivity was obtained when potassium /tr/-butoxide in the presence of dicyclohcxyl-18-crown-6 was employed. In the absence of crown ether the diastereoselection was poor and the sense of the stereochemical outcome was reversed26. 

VL,3S,6R)-2,3,4,6-tetrahydro-3,4-dimethyl-6-(2-nitrocyclohexy[)-2-phenyl-1,4-oxazepine-5,7-dione ... 

In a further example of a multicomponent synthesis, dihydrobenz[/] 1,4 oxazepin-5-ones were prepared in good yields in two steps by combining an initial three-component Ugi condensation with a subsequent Mitsunobu cyclisation to give (124 e.g. R1 = H, R2 = i-Pr, R3 = cyclohexyl, 65%) <06OBC4236>. 

A ring enlargement process was used effectively to access the enantiopure pyrrolo [ 1,4]oxazepine-9a(7//)-carboxylate derivatives 142 and 143. The sequence involved copper (Il)-catalysed decomposition of an a-diazocarbonyl derivative attached to a chiral morpholinone, and a carbenoid, spiro-[5,6]-ammonium ylide, Stevens [1,2] rearrangement sequence. The Stevens and related rearrangements have considerable further potential for novel heterocyclic syntheses <00TA3449>. 

The effect of the riot control agent dibenz(b,f)-1,4-oxazepine (CR) in the rabbit eye. Toxicol. Appl. Pharmacol. 34 45-48, 1975. 

Many of the most useful syntheses of 1,4-oxazepines are of this type. Either the N—C or the O—C bond may be formed first depending on the nature of the substituents on N and O and in most cases the intermediate of type C—C—N—C—C—C—O or N—C—C—C—O—C—C can be isolated. In this treatment the examples are presented in that order. 

Dibenz[6,/][ 1,4]oxazepines, which have intense lachrymatory and skin irritant properties, can be prepared in high yield by the Bischler-Napieralsky-type cyclization of N- 2-phenoxyphenyl)formamides (76JCS(P1)1279>. 

Oxazepines fused to heterocyclic rings have been prepared by the reaction of ethanolamine for example with 4-chloro-3-ethoxycarbonylpyridine (71CPB2354) to give... 

There has been little systematic study of the chemistry of 1,4-oxazepines. Vigorous acid hydrolysis cleaves the amide linkage in (369 R1=Ph, R2 = H) and recyclization gives 2-o-hydroxyphenyl-5-phenyloxazoline and l,2,3,4-tetrahydro-l,8-dihydroxy-3-phenyl-isoquinoline. The l,4-benzoxazepin-5-one (353) can be alkylated at N but on treatment with triethyloxonium fluoroborate it is converted to 5-ethoxy-3-phenyl-l,4-benzoxazepine — one of the very few examples of a fully unsaturated 1,4-oxazepine ring. This product is isomerized to l-ethoxy-4-hydroxy-3-phenylisoquinoline when boiled in methanol. The 4,l-benzoxazepine-2,5-diones (348) are converted to quinazolines by reaction with ammonia. The dihydro-l,4-oxazepin-5-one (343) can be acetylated at nitrogen and bromi-nated at the 6-position. 

As with 1,4-oxazepines the Schmidt reaction of cyclic ketones and the Beckmann rearrangement of their oximes can be applied to the synthesis of monocyclic 1,4-thiazepines, 1,4- and 1,5-benzothiazepines and their 1-oxides and 1,1-dioxides (75CJC276). 

Likewise, 1,4-diazepine 5i-m,83 1,4-thiazepine 5h,83 1,4-oxazepine 5a-g,83 and 1,4-oxazepin-5-one92 derivatives were formed in good yield on thermolysis of suitably substituted dihetera-tricyclo[3.2.0.02,4]heptanes in refluxing toluene or xylene. 

Pyridine is easily converted into 2-azabicyclo[2,2,0]hex-5-enes (358), which can be further transformed into useful 3-aza-7-oxatricyclo[4,l,0,02 5]hept-3-enes (359). Irradiation of (359) in acetonitrile gives the corresponding novel 1,4-oxazepines (360) in 90-95% yield (Scheme 49). This type of valence isomerization has been applied to the synthesis of fully aromatized 1,4-epines with two heteroatoms, such as 1,4-oxazepines, 1,4-thiazepines, 1,4-diazepines, and azepines (85CPB4572, 86CC1188, 87H(26)3085, 87JOC5247, 90CPB2911, 90TL20>. 

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