L,4-Benzoxazepine-5 -ones

The 5a-alkyl-l,2,5a,8,ll,lla-hexahydro-3/f,5//-pyrrolo[2,l-c][l,4]benzoxazepin-5-ones 1 and the l-[(l-alkyl-2-methoxy-2,5-cyclohcxadienyl)carbonyl]-2-(methoxymethoxymethyl)pyr-rolidines 2 can be rearranged and protected. The keto esters 3 thus obtained have been used as chiral synthetic intermediates28,32. 

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. 

The Schmidt reaction is conducted+in strong acid and the essential step is the attack by the nucleophilic hydrazoic acid, HN —N=N on the carbonyl group. Chromanone is converted into l,4-benzoxazepin-5-one (644) but a few chromanones give the l,5-benzoxazepin-4-one (645) while others produce both types of oxazepines <77HC(31)207). 

The acetal 1, obtained from salicylamide and bromoacetaldehyde diethyl acetal, cyclizes on heating to provide l,4-benzoxazepin-5(4//)-one (2).32... 

Freedman and Huber showed that the cyclization of 253 with NaH/DMSO did not afford 3-methyl-l,4-benzoxazepin-5(4//)-one 255, as previously reported. Instead, they isolated 2-(2-hydroxyphenyl)-5-methyloxazole 256 and confirmed the structure by independent synthesis from 2-hydroxy-A -(2-propynyl)benzamide 257 (Scheme 1.69). The authors considered an intermediate allene but were not able to unequivocally establish the mechanism for conversion of 253 to 256. 

The reactions of anthranilic acids and esters (65CB983, 75BSF(2)283) with halohydrins give the 4,l-benzoxazepin-5-one system (357). o-Methylaminobenzamide reacts with ethylene oxide to give (358) which can be cleaved to (359) by treatment with aqueous ammonia (66JOC4268). 

Reactions of this type have been widely used for the synthesis of 1,5-benzoxazepines by the reactions of o-aminophenols and their derivatives with a variety of functionalized three-carbon chains. Thus reaction with 3-bromo-l-chloropropane gives (360) and reaction with 3-chloropropionyl chloride gives the analogous 4-oxo derivative. Similarly a,/3-unsatur-ated Icetones give (361), /3-ketoesters give (362), l,3-oxazolid-5-ones give (363), and the reaction of the sodium salt of N-methanesulfonyl-o-aminophenol with epichlorohydrin gives... 

Benzoxazepines are prepared similarly from o-aminophenols . 2-Aminophenol with 1,3-dibromopropane gives 1,4-benzoxazepine 395 and 3-chloropropionyl chloride gives the analogous 4-oxo derivative. Similarly, -unsaturated ketones give 396, -keto esters give 397, and l,3-oxazolidin-5-ones give 398. 

Scheme 2 8-Methoxy-4,5-dihydro-l,4-benzoxazepin-2(3/t)-one Derivative Intermediate in the Activation of N -Protected A -(2-Hydroxy-4-methoxybenzyl) Amino Acids ...

A further development of this safety-catch principle led to A -[2-hydroxybenzyl-4-methoxy-5-(methylsulfinyl)] (SiMB) derivatives (Scheme 4) where the acylation potency of the intermediate 8-methoxy-4,5-dihydro-l,4-benzoxazepin-2(3//)-one derivatives (Scheme 2) is significantly enhanced and similarly the rate of intramolecular O N acyl migration. The related Fmoc-protected amino acid derivatives are readily prepared and cleavage is achieved by reductive acidolysis (SiCl4/TFA/anisole/ethandithiol 5 90 2.5 2.5, 2h at room temperature). 

A small library of 4,5-dihydro-l,4-benzoxazepin-3(2/f)-ones was prepared by polymer assisted solution phase synthesis based on saheyhe aldehydes, a-bromoaeetie acid esters and primary amines <05MI643>. As noted previously, pyrimido[4,5-fe][l,4]-benzoxazepines (and diazepines, and thiazepines) can be accessed via a neat variation of the Pictet-Spengler cyclisation. The compounds are of interest as inhibitors of particular receptor tyrosine kinases <05JOC9629>. Liu et al. have also reported a synthesis of 5,6-dihydro-pyrimido[4,5-Z)][l,4]benzoxazepines 173, 174 based on a cyclocondensation of the imines 172 <05TL7523>. The advantage of the approach was the incorporation of poorly reactive pyrimidyl amines 170,171. 

---