Oxepins ester

Oxepin-2-carboxylic acid, methyl ester H NMR, 7, 552 <79JA2470)... 

Due to the nonaromatic character of the oxepin system the oxepinones do not usually form stable enol structures. By O-acylation or O-alkylation, however, the enol forms can be stabilized as enol esters and ethers, respectively. A large number of substituted 1-benzoxepins have been synthesized by this route. Acetylation of l-benzoxepin-3(2//)-ones 1 and l-benzoxepin-5(2/T)-ones 3 was readily achieved with acetic anhydride in the presence of an appropriate base such as pyridine, triethylamine or sodium acetate.t5,t6 t72 176... 

In general, the O-alkylation of benzoxepinones is accomplished via the anion. Alternatively, an acid-catalyzed process employing ortho esters may be used. For the acid-catalyzed formal O-alkylation of l-chloro-8-methoxydibenz[ft,/]oxepin-10(ll//)-ones with triethyl orthoformate rather drastic conditions are required (hot concentrated sulfuric acid) to give the 10-ethoxy derivative 12 in excellent yield.109... 

Ring enlargement via an insertion of a carbene generated in the a-position to the ring is an established method and has also been applied to the synthesis of oxepins. The ()3-allylpalladium chloride catalyzed decomposition of substituted ethyl diazo(4/7-pyran-4-yl)acetates in benzene at room temperature gives ethyl oxepin-4-carboxylates 1 in excellent yield.190 The ester function can be replaced by the phosphonate group and other P = 0-functions (see Houben-Weyl,... 

Occasionally, addition products of 4//-l,2,4-triazole-3,5-diones or diazenedicarboxylic esters and oxepins have been obtained whose formation can be rationalized by an addition to the 2,4-diene system in the oxepin, e.g. formation of 10.190191 In these cases, the primary adduct usually cannot be isolated, because it undergoes a hetero-Cope rearrangement to a tricyclic or bicyclic structure in which the oxepin oxygen has become part of a carbonyl function.190 191,227... 

Irradiation of 3,6-bridged oxepins with ester functions in the 4- and 5-positions gives tricyclic structures 3 in which the oxepin oxygen becomes part of an aldehyde function.248-250 When chiral esters are used, it has been shown that the irradiation in solid state proceeds with a high degree of diastereoselectivity.249,251,252... 

The 7-azaquadricyclane (77), like its precursor (12), shows evidence in the NMR spectrum of restricted rotation about the N-CO bond. All the 7-heteroquadricyclanes, 76-79, are thermolabile, and they rearrange very readily to the corresponding azepines (80) or oxepin (81). (In another instance the 7-oxabicyclo[4.1.0] valence-bond tautomer was obtained instead. ) In appropriate conditions the addition of acetylenic esters (methyl propiolate and dimethyl acetylene-dicarboxylate) competes successfully with the isomerization and gives the ca o-tricyclic adducts 82 or 83. " °... 

The initial 6,ll-dihydrodibenz[b,e]oxepin-ll-one (7.1.9) is synthesized from the ethyl ester of 2-phenoxymethyl benzoic acid (7.1.7), which is easily synthesized by reacting ethyl 2-bromomethylbenzoate with phenol in the presence of a base. The resulting ester (7.1.5) is hydrolyzed into 2-phenoxymethylbenzoic acid (7.1.8), which is cyclized to 6,11-dihydrodibenz[b,e]oxepin-ll-one (7.1.9) by trifluoroacetic acid anhydride. 

An attempted synthesis of 9-methylnaphtho[crf]oxepine-2-one 494 by heterocyclization of 8-acetyl-1-naphthoic acid 491 (R = Me, R = H) has failed. In acidic medium or on heating acid 491 to 150°C, as well as under formation conditions for the acid chloride or ester from acid 491, 2-acetylacenaphthene-l-one 495 is obtained (79ZOR1562). A synthesis of tribenzo[c]oxepine derivatives 499 and 501 has been described as resulting from heterocyclization of the products of reduction (498) or oxidation (500) of 4-formyl-5-carboxyphenanthrene 497. The latter compound was obtained on ozonolysis of pyrene 496 [71JCS(C)729]. 

A soln. of startg. ester in dichloromethane treated with 2 eqs. SnC at —70° for 15 min, and the mixture allowed to warm slowly to room temp, over 2 h - product. Y 58%. Reaction is thought to proceed via a cationic oxa-Cope rearrangement. F.e, inch oxepin analogs, also satd. O-heterocyclics from ethylenic derivs., and 3-vinyl-tetrahydrofuran-2-carboxylic acid esters with an allylsilane group as internal nucleophile, s. L.D.M. Lolkema et al.. Tetrahedron Letters 29, 6365-8 (1988). 

Carboxymethyl-S-ethoxyoxazole reacts with fumaronitrile to give 4,5-di-cyano-2-methyl-3-pyridinol. ° It reacts with 4,7-dihydro-l,3-dioxepine to give W-294, which is hydrolyzed with dilute hydrochloric acid to pyridoxine. The ethyl ester of Coarboxymethyl-5-ethoxyoxazole reacts with 1,3-dioxepine to form XII-294 and Xn-295, which can also be hydrolyzed to pyridoxine. S-Cyano-4-methyloxazole and 4,7-dihydro-l,3-oxepines have been used to... 

Although taxanes are promising natural precursors of pachtaxel, the formidable task for the chemists was to selectively hydrolyze the amide bond while retaining the four hydrol5 tically more sensitive ester groups, one at the particularly reactive allyhc position, and one highly strained oxepine ring. Obviously, any acid or base catalyzed hydrolysis was too non-specific, whereas enzymatic hydrolysis by peptidases or amidases is known to be rather inefficient with such complex substrates [47],... 

SCHEME 13.15 Ring-opening of an ester functionalized 1,2-cyclopropane derivative 50 to oxepine 51 [28],... 

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