Benzoxazepine

The parent 1,4-benzoxazepine is very unstable it and its simple derivatives have been reported only recently. 

Kamei K, Maeda N, Nomura K, Shibata M, Katsuragi-Ogino R, Koyama M, Nakajima M, Inoue T, Ohno T, Tatsuoka T. Synthesis, sar studies, and evaluation of 1,4-benzoxazepine derivatives as selective 5-htla receptor agonists with neuroprotective effect discovery of piclozotan. Bioorg Med Chem 2006 14 1978-1992. 

Via (N—C—C—C—O—C—C) intermediates (type c). Salicylamide (351 R = H) can be converted to 1,4-benzoxazepine derivatives, e.g. its reaction with 2-chloropheny-lacetic acid gives (351 R = CH(Ph)C02H) which on treatment with acetyl chloride cyclizes to the 3,5-dione (352). Similarly reaction of (351 R = H) with phenacyl bromide gives (351 R = CH2COPh) which undergoes acid-catalyzed cyclization to give (353). 

Pyridazino[4,5-A]oxazepines 295 are 5-HTia receptor ligands <1997BML2857>. The 5-HT1A receptor plays a role in psychiatric disorders such as anxiety and depression. 1,4-Benzoxazepine 296 is a 5-HT1A antagonist and exhibits highly potent anti-ischemic effects <2001BML595>. 

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. 

---