1.4- Benzoxazepines 2,3,4,5-tetrahydro

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. 

A-Acyl-l,3,4,5-tetrahydro-2,1 -benzoxazepines (268) are synthesized from the A-chloro derivatives (267). The reaction proceeds via initial ipso attack followed by 1,2-carbon migration (84JCS(P1)2255, 87T2577, 90T7247). 

The 2,3-benzoxazepin-l-one system (436) is prepared by the reaction of benzonitrile oxide with the benzopyranone (435) (80JCS(P1)846). The tetrahydro-3,2-benzothiazepine 3,3-dioxide (438) was prepared from (437) by intramolecular sulfonamidomethylation (76CC470). 

The best solvent, temperature, and Lewis acid conditions for the Sn reactions of CRS)-l-(2-mtrobenzenesulfonyl)- and (7 5 )-l-(4-nitrobenzenesulfonyl)-3-methoxy-l,2,3,5-tetrahydro-4,l-benzoxazepines with silylated 5-fluorouracil and uracil129 proved to be SnCL at 50 °C in MeCN. The more nucleophilic silylated uracil reacts faster at its N(3) atom giving mainly the cyclic 0,N-acetal (by C-OMe cleavage). The silylated 5-fluorouracil, on the other hand, reacts at its less sterically hindered N(l) atom and gives mainly an acyclic product (by ring C-0 cleavage). Calculations at the HF/6-31G level of theory support the experimental observations. 

The N—0 bond in the tetrahydro-2,3-benzoxazepine (27) can be cleaved reductively either directly using zinc in acetic acid to give (29) or stepwise via the methiodide salt (28) to give (30). The secondary amino alcohol (29) can be converted readily to (30) (Scheme 1). The N—O bond in (28) can also be broken under basic conditions in a Hofmann-like elimination to afford the amino ketone (31) (Equation (2)) <80AJC833>. 

Tetrahydro-l,4-benzoxazepine JV-oxide (38) underwent smooth ring expansion under thermal conditions in acetonitrile to give 3,4-dihydro-2//,6/f-l,5,4-benzodioxazocine (39) in yields of 60-95% (Scheme 15) <88AJC293>. 

Matyus et al. described a cascade Knovenagel/1,5-hydride transfer/cyclization reactions of 4-aryl-2-phenyl-1,4-benzoxazepine derivatives 19, which furnished fused 0,A -heterocycles 20 containing tetrahydro-l,4-benzoxazepine and tetrahydroquinoline moieties with high yields and diastereoselectivity (Scheme 9) [92]. Basically, under thermal conditions, the benzylidene intermediate I generated in situ... 

Benzophenone refluxed 3 days with 2 g.-atoms Li-wire in ether, 2-methylquinoline added, heating continued 2 days, then water added l,2,4,5-tetrahydro-2-methyl-2,5-methano-3,l-benzoxazepine (Y 76.2%) suspended in 70%-H2SO4, heated 12 hrs. at 75°, cooled, digested with water, and stirred with 2 N NH3 2-methyl-4-(diphenylmethyl)quinoline (Y almost 100%). F. e. s. C. E. Crawford, O. Meth-Cohn, and C. A. Russell, Soc. Perkin 11972, 1176. 

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