Oxazepin-7-ones

An alternative ring construction approach to 1,4-oxazepin-7-ones (e.g. 241) utilises the Baylis-Hillman product 240, subsequent reaction with a p-aminoalcohol, and ester hydrolysis followed by DCC-mediated intramolecular coupling to afford 241. This sequence can be generalised to give a range of analogues [02S2232],... 

A new synthesis of optically active 3-substituted 1,4-oxazepin-7-ones 88 (e.g. R " = CF3, R = H) from 87 has been reported by Richard et al. <03HCA726>. 

A number of combinatorial-based syntheses have been reported. Andrus et al. prepared a solution-phase indexed combinatorial library of nonnatural polyenes such as 291 for multidrug resistance reversal.298 This library was formed by modification of R and R. Ellman and co-workers reported a combinatorial library of synthetic receptors targeting vancomycin-resistant bacteria,209 and Paterson et al. prepared polyketide-type libraries by iterative asymmetric aldol reactions on solid support.2l0 Rieser et al. used combinatorial liquid-phase synthesis to prepare [1,4]-oxazepine-7-ones by the Baylis-Hillman reaction (see sec. 9.7.B).2H Schreiber and co-workers reported the synthesis and evaluation of a library of polycyclic small molecules for use in chemical genetic assays.2 2 Bauer et al. reported a library of N-substituted 2-pyrazoline compounds... 

Thermolysis of 3-oxa-6-azatricyclo[3.2.0.02,4]heptan-7-ones 4 results in valence isomerization to yield 1,4-oxazepin-5(4/f)-ones 5 31... 

Heating phenacyl 2-aminobenzoate with phosphoryl chloride yields 2-phenyl-4,1-benz-oxazepin-5(17/)-one (1. R = H). The method has been applied to the synthesis of a number of analogs.423... 

Dibenz[6,/][l,4]oxazepin-ll(10//)-ones 4 are formed in near quantitative yield by cycli-zation of aryl 2-isocyanatophenyl ethers 3 in the presence of aluminum trichloride. Exact yields were not reported.40... 

Treatment of the 1,2-oxazines 52 with carbon monoxide at 1000 psi in the presence of cobalt carbonyl brings about insertion of carbon monoxide to form the 1,3-oxazepines S3 <96TL2713>. A convenient route to P-lactams fused to oxepines is made available by alkene metathesis. Thus reaction of 4-acetoxyazetidin-2-one with ally alcohol in the presence of zinc acetate, followed by iV-allylation of the nitrogen affords the derivative 54 which cyclises by RCM to form the oxazepinone 55 <96CC2231>. The same communication describes a similar synthesis of 1,3-dioxepines. 

Principal components analysis can also be used in the case when the compounds are characterized by multiple activities instead of a single one, as required by the Hansch or Free-Wilson models. This leads to the multivariate bioassay analysis which has been developed by Mager [9]. By way of illustration we consider the physicochemical and biological data reported by Schmutz [41] on six oxazepines... 

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>. 

Racker et al. have developed an interesting new combinatorial method for the synthesis of [l,4]oxazepin-7-ones (eg 139, R = Ph) from aldehydes and a-amino alcohols with the Baylis-Hillman reaction being a key step . 

One-step reduction of aldehyde and ester functions in intermediate 263a (R = Me, = H) results in a di-alcohol, which, when treated with P2O5, undergoes cyclization into oxazepine 264 (Scheme 56 (2005BMCL2515)). Similarly, this reaction sequence can start from monoester 263b (R = H, r2 = OH (2001JCS(P1)1039)). 

Aminobenzo[i7]thieno[2,3-/][l,4]oxazepin-10(9H)-one 278 forms 7-fluoro derivative 279 by a standard diazotation/fluorination procedure (Scheme 59, Section 3.2.3 (1992AF896, 2002JHC163)). 

Tetramethyl-l,2-oxazepin-5-one and its N- methyl analogue have been prepared by the addition of hydroxylamine and N-methylhydroxylamine to phorone (73TL1615). 

The unstable dibenz[c,/][l,2]oxazepines (312 R = CN, Cl) have been isolated as the major products of the UV irradiation of 9-cyano- and 9-chloro-acridine 10-oxides (310) in benzene (c/. the analogous Af-imide to 1,2-diazepine conversion on p. 598). Although none of the oxaziridine tautomer (311) was detectable by UV spectroscopy, the subsequent deoxygenation of (312) to acridine suggests the existence of a thermal equilibrium between (311) and (312) (79T1273). These dibenzo compounds (312) are the only fully unsaturated oxazepines yet isolated but the 2,3-benzoxazepin-l-one system (314) has recently been prepared by the reaction of benzonitrile oxide with the benzopyranone (313) (80JCS(Pl)846). 

Monocyclic 1,3-oxazepines (325) with aryl substituents at the 2-, 4- and 7-positions can be prepared in moderate yield (20-40%) by the reaction of aliphatic diazo compounds with 1,3-oxazinium perchlorates (324) (74S187). Tetra- and penta-phenyl-l,3-oxazepines (328 R = H or Ph) have been obtained via the reaction of azide with pyrylium salts (326) (78H(l 1)331). This principle had earlier been applied to the preparation of 1,3-benzoxazepines (74CR(C)(278)1389> and more recently to 3,1-benzoxazepines (81JHC847). The preparation of 2-phenyl-1,3-oxazepine.(331) by the UV irradiation of (329) is mechanistically interesting in that it apparently involves an intermediate (330) of the same type as (327) (73TL1835), but the method has only been used in this one case. One of the few examples of a dihydro-1,3-oxazepine (333) has been prepared by the thermolysis of the aziridine (332) (68JOC4547). 

A range of 2,2-bis(trifluoromethyl)-l,3-oxazepin-5-ones (334) has been prepared by the reaction of oxazolidin-5-ones with 1-diethylamino-l-propyne (75TL3223). l,3-Oxazepan-2-one has been prepared by the Beckmann rearrangement of tetrahydro-2-pyranone oxime. 

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). 

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