Synthesis of 1,2-Oxazepines

Chen and Zhao reported an interesting coupling reaction of A/-phenoxyacetamides with a, -unsaturated aldehydes to give 1,2-oxazepines 120 by C-H activation and [4-1-3] annulation (Eq. (5.111)) [57]. This simple [4-1-3] annulation method features mild reaction conditions and high product yields for various substituted 

N-phenoxyacetamides and , -unsaturated aldehydes. However, use of cin-namaldehyde or a-methyl unsaturated aldehyde substrates resulted in no reaction. Finally, product 120d underwent a reduction reaction under a H2 atmosphere to afford the unusual benzofused chroman derivative 121 in 80% yield. 

In recent years, research in the field of Rh catalysis has resulted in the development of numerous transformations that provide various nitrogen heterocycles. Most of the transformations result in the formation of a C-N bond with good to excellent yields, in addition to good stereocontrol. Despite the many developments that have been made in this arena, new findings are being reported with greater frequency. This research area will potentially remain a fruitful discipline for many years to come. In particular, the development of new Rh catalysts and Rh-catalyzed reactions will likely take a lead role, with more attention on the scope and application of the transformations. In addition, studies on the catalytic reaction mechanisms to understand the nature of the reactions will continue for some period. 

(a) Suzuki, A. (1998) in Metal-Catalyzed Cross-Coupling Reactions (eds F. Diederich and P.J. Stang), Wiley- 

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RCM methodology can be used for the synthesis of 1,2-oxazepine derivatives. Thus, compounds 189 and 191 were prepared in good yields from the respective diene precursors 188 and 190 both accessed in turn from 187 (Scheme 92) C2003SL1043, CHEC-III(13.07.3)239>. 

An efficient synthesis of 1,2-oxazepines from Af-phenoxyacetamides and a, P-unsaturated aldehydes under room temperature through Rh(III)-catalyzed intermolecular [4+3] aimulation was reported by Zhao and coworkers (Scheme 6.32) [47]. It is worth noting that 1,2-oxazepine is readily transformed to chroman... 

Scheme 6.32 Synthesis of 1,2-oxazepines from N-phenoxyacetamides and a,p-unsaturated aldehydes.

To the best of our knowledge, no procedure has been reported since 1995 for the synthesis of 1,4-oxazepines from [5+2] fragments without isolating the intermediate. 

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. 

The Meisenheimer rearrangement of tertiary amine N- oxides has been applied to the synthesis of both monocyclic 1,2-oxazepines, e.g. (309) (65JOC3135, 65JCS1653, 82H(19)173), and those fused to benzene (80AJC833) and a variety of heterocyclic rings (80AJC1335). 

Ring-closing metathesis methodology has been used in the synthesis of the 1,2-oxazepine derivatives 21 and 22. These derivatives were synthesized from the respective diene precursors 20 and 19, which were derived from 18 by N-acylation or N-alkylation respectively (Scheme 1) <2003SL1043>. 

The synthesis of perfluorinated 1,2-oxazepines 33 and 34 was carried out through unusual cyclocondensation process. The reaction of hydroxy lamine with excess of 16 resulted in the formation of 1 2 adduct—1,2-oxazepine 33 in 50% yield, along with smaller amount of by-product 34 (derived from 33 as the result of HF addition across the C=C bond (Fig. 10.15), while the expected 5-fluoro-3-(pentafluoroethyl)-4-trifluoromethylisoxazole is formed in this reaction only as a minor by-product. Several 2,2-bis(trifluoromethyl)-l,3-oxazepines were prepared using an interesting reaction of 2,2-bis(trifluoromethyl)-l,3-oxazolidin-5-ones (35) and 1-diethyla-minoprop-l-yne. This reaction results in a high-yield formation of the corresponding 2-bis(trifluoromethyl) l,3-oxazepin-5-ones 36 (Fig. 10.16). 

In the second synthesis,20 l-(2-acyloxyphenyl)-2-azidoethanones 3 cyclize to 1,3-benz-oxazepin-5-ols 4 in the presence of triethyl phosphite. As in the previous reaction, the intermediate phosphorus compounds are not isolated. 

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... 

Other quinoline A-oxide derivatives have been examined. A 1,3-oxazepine is the major product of irradiation of 2-cyanoquinoline A-oxide whereas lactam formation predominates on irradiation of 4-methylquinoline N-oxide in aqueous ethanol.60 Lactam formation has been shown to be influenced by an external magnetic field and on this basis it has been proposed that the first step in this transformation is the formation of an excited radical-ion pair.61 1,3-Oxazepines undergo further reaction on prolonged irradiation. The synthesis of 4-substituted indoles, for example, has been accomplished in this way by irradiation of 5-substituted quinoline A-oxides.62... 

A 1,3-oxazepine derivative (158) has been isolated in low (2-3%) or unspecified yield by treatment of the Z-ketovinylazirine 157 with diiron nonacarbonyl50 or molybdenum hexacarbonyl,51 respectively (Scheme 182) the major products of these reactions are pyrrole derivatives (see Scheme 23 in Section IV,A,1). There is no preparative value in this type of oxazepine synthesis (Scheme 182) since the transformation can be affected efficiently in a thermal reaction at 100°C.52... 

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>. 

This procedure is similar to the previous one, except that the cyclization happens on the carbon at the /3-position of the nitrogen atom. The synthesis of oxazepine 145 started with the reaction of 4,4 -dichloro-2-methyl-3-(2//)-pyridazinone 142 with 3-benzylamino-l-phenylpropen-l-ol 143. The obtained product 144 was cyclized in basic conditions to the desired 1,4-oxazepine 145 (Scheme 20) <1996JHC583>. 

Asymmetric synthesis of cyclopropanes, The reaction of dimethyloxosnifonium methylide with (E)-(2R,3S)-6-alkylidene-3,4-dimethyl-2-phenylperhydro-l,4-oxazepine-5,7-diones (1) yields cyclopropane derivatives (2) and dihydrofuranes (3). The ratio of the products depends on the solvent and temperature. Use of THF at 25° favors formation of 2, whereas formation of 3 is favored by use of DMF at -61°. The products (2 and 3) can be converted into optically pure cyclopropane-1,1-dicarboxylic acids (4) and 3-substituted y-butyrolactones (5), respectively. 

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... 

The reaction ofa chiral 5,7-dioxoperhydro-l,4-oxazepine withcyclopentene-l,2-dionedimer(21) in the presence of triethylamine in refluxing dichloromethane afforded one pure stereoisomer of the 2,1-trans Michael adduct in 60% yield <90TL20,90TL2033), which has been used as key intermediate for the asymmetric synthesis of virtually all monoterpenoid alkaloids and secoiridoids (Scheme 6)... 

Intramolecular photoamination was applied to the synthesis of heterocyclic compounds. Photoamination of 9-(4-amino-l-butoxy)phenanthrene (Id) gave phenanthro[9,70-b] -oxazepine derivatives (38) in a cis to trans isomer ratio of 65 35, along with 4-[A-(9-phenanthrylamino)]butanol (39) (Scheme 6.35) [39]. Recently, Lewis and coworkers applied photoamination to the intramolecnlar amination of o-(3-aminoethyl)stilbenes (40a), which gave l-benzyl-1,2,3,4-tetrahydroisoquinoline (41a 76%) [55]. Similarly, photoamination of o-(3-aminopropyl)stilbenes (40) afforded benzazepine derivative (41 70%) (Scheme 6.36). Also the aporphine and azepine prepared the intramolecular photoamination of l-(aminoaIkyl)phenanthrenes [56]. 

Heravi et al. (2006) have studied the synthesis of 2-phenyl-3-hydroxy-quinolin-4(lH) under microwave irradiation in solventless system. It was a two-step synthesis. Anthranilic acid, phenacyl bromide and potassium carbonate were exposed under microwaves in solventless media to produce phenacyl anthranilate (within 2 min), where as the same product was obtained in 1 h under conventional heating. Final product 2-phenyl-3H-benz-[e] [1,4] oxazepin-5-one was prepared in very short time of only 2 min when phenacyl anthranilate was treated further with polyphos-phoric acid supported on silica gel. 

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