Heterocyclics oxepines

Ethylene oxide 3 may be cyclodimerized to 1,4-dioxan 4 in the presence of superacids, like chlorosulfonic or perchloric acid (Equation 1). The reaction was accelerated by aprotic dipolar solvents, but was retarded by less polar solvents. Chlorosulfonic acid also catalysed ring-opening polymerization of the saturated oxygen heterocycle oxepine 5 to the polymer 6 (Equation 2). ... 

Oxepin is the Hantzsch-Widman name for a seven-membered unsaturated heterocycle with one oxygen atom and the numbering follows the convention for monocyclic heterocycles. However, the isomeric benzene oxide has different numbering in agreement with the 7-oxabi-cyclo[4.1.0]hepta-2,4-diene structure, position 1 now corresponds to position 2 in the oxepin. 

A number of oxepin derivatives with alkano bridges across the 3- and 6-positions and across the central C-C double bond have been oxidized with ruthenium(VIII) oxide. Usually, all of the double bonds of the heterocycle are cleaved and a macrocycle 5 is formed that contains two 1,2-diketone functions.142,199... 

Numerous reactions have been described in which the oxygen of the oxepin system is removed to give benzene derivatives. The formation of the aromatic products can be rationalized by an arene oxide as intermediate. A suitable reagent for the elimination of an oxygen atom from this heterocycle is triphenylphosphane, e.g. formation of l,24 2a,12 and 2b.1,9... 

Due to the instability of the seven-membered heterocyclic ring, oxepin is prone to isomerization reactions to bicyclic heterocycles such as benzene oxide. Irradiation of oxepin with UV light of/. > 310 nm gives the isomeric 2-oxabicyclo[3.2.0]heptadiene(l) in high yield.12 207 At shorter wave lengths, phenol is formed predominantly.207... 

When the hydride ion of lithium alanate is used as nucleophile, cyclohexa-2,4-dien-l-ol is obtained as a labile addition product which eliminates water on standing to give benzene.12 The reaction of an oxepin derivative that possesses a hexamethylene bridge across C3-C6 with sodium methoxide gives an addition product 5 in which the seven-membered heterocyclic system is retained.213 214... 

Cleavage of the heterocycle is observed when oxepin reacts with l-chloro-4-nitrosobenzene to give 4-chloro-AL(6-oxohexa-2,4-dienylidene)aniline iV-oxide (6) in 62% yield.215... 

Interestingly, in the inverse-electron-demand Diels-Alder reactions of oxepin with various enophiles such as cyclopentadienones and tetrazines the oxepin form, rather than the benzene oxide, undergoes the cycloaddition.234 236 Usually, the central C-C double bond acts as dienophile. Oxepin reacts with 2,5-dimethyl-3,4-diphenylcyclopenta-2,4-dienone to give the cycloadduct 6 across the 4,5-C-C double bond of the heterocycle.234 The adduct resists thermal carbon monoxide elimination but undergoes cycloreversion to oxepin and the cyclopenta-dienone.234... 

The 1,3-dipolar reagent diazomethane reacts with oxepin and substituted derivatives to afford 1 1 or 2 1 adducts 13 or 14 across the C-C double bonds of the isomeric benzene oxides.238 239 In the 1 1 addition product 13, the two heterocycles adopt a cis orientation.238 The nitrogen can be extruded by irradiation of the dihydropyrazole. 

The light-induced reaction of pentacarbonyliron with oxepin or 2,7-dimethyloxepin results in the formation of small quantities (3-5 %) of a tricarbonyliron complex of the seven-mem-bered heterocycle.253,251 The main products are benzene (o-xylene) and phenol (2,6-dimethyl-phenol). When 1-benzoxepin is treated with pentacarbonyliron, the tricarbonyliron complex is obtained in 22% yield.254... 

The availability of non-racemic oxepins through tandem catalytic RCM and Zr-catalyzed kinetic resolution has additional important implications. Optically pure heterocycles that carry a heteroatom within their side chain (cf. (S)-14 in Scheme 3) can be used in stereoselective uncatalyzed alkylations. The alcohol, benzyl ether or MEM-ethers derived from (S)-14 readily undergo directed [10] and diastereoselective alkylations when treated with a variety of Grignard reagents [11]. 

Another isomerization reaction of arene oxides is equilibrium with oxe-pins [5], Here, the fused six-membered carbocycle and three-membered oxirane merge to form a seven-membered heterocycle, as shown in Fig. 10.2. An extensive computational and experimental study involving 75 epoxides of monocyclic, bicyclic, and polycyclic aromatic hydrocarbons has revealed much information on the structural factors that influence the reaction rate and position of equilibrium [11], Thus, some compounds were stable as oxepins (e.g., naphthalene 2,3-oxide), while others exhibited a balanced equilibrium... 

Among the valence-bond isomerisations leading to heterocyclic systems, the synthesis of derivatives of azepine (22) and oxepin (28) have been specially successful (Scheme 6.13) [32]. 

Table 3.20 lists examples of the preparation of oxygen-containing heterocycles by RCM. Further examples, including lactones [895], pyrans [896,897], chromenes [839], tetrahydrofurans [838], phosphonates [898], and oxepines [856,899-902], have been reported. For references to macrocyclizations see Scope and Limitations in this section. 

The nomenclature and numbering used above are recommended by lUPAC (1998PAC143), and they can be further applied to the other cyclic systems with one or more heteroatoms on the heteropine ring using the order of preference rules. Thus, fusion of pyrrole (54), furan (71) or thiophene (78) with azepine (43), oxepine (67) or thiepine (78) results in chemical names in which the parent heterocycle has the lowest preference number and is cited last in the name (preference numbers from Appendix II (1998PAC143) are in brackets). Explanation of the fusion descriptors can be found in the lUPAC recommendations (1998PAC143) and were exemplified in CHEC-I (1984CHEC-1(1)7). 

Flash vacuum pyrolysis of oxiranes 156, accessible by a two-step procedure, results in carbonyl ylides 157, conjugated with a diene system formed by benzene and heterocyclic substituents R. They further undergo 1,7-electrocyclization and subsequent 1,5-sigma tropic hydrogen shift to give oxepines 158 and 159 (Scheme 31 (1997JCS(P1)3025, 1996JCS(P1)515)). 

Fully unsaturated seven-membered heterocyclics have alternating bond lengths and are normally in boat conformations. Ring inversion barriers are 42.7 kJ mol-1 for 3-methyl-3ff-azepine and 35.6 kJ mol-1 for 3//-azepin-2-one (CHEC 5.16.2.3). The barriers for oxepin and thiepin are somewhat lower. Annulation can introduce large conformational barriers, to the extent of making possible the resolution into enantiomers of a tribenzoxepin (71CB2923). 

The heterepine-heteronorcaradiene equilibrium exemplifed for oxepin in Scheme 2 represents perhaps the best known type of valence tautomerism met in seven-membered and larger heterocyclics. 

Carbon-13 shift of common non-aromatic heterocycles with endo- and exocyclic double bonds are reviewed in Table 4.66 [416-432], - Deshieldings of / -carbons induced by carbonyl groups in heterocyclic a, /1-enones due to (—)-M electron withdrawal (e.g. 2-pyrones, coumarins) and shieldings of [ carbons in cyclic enol ethers arising from (+ )-M electron release (e.g. 2,3-dihydrofuran and oxepine derivatives in Table 4.66) fully correspond to the effects described for the open-chain analogs. Outstandingly large shift values are observed for the lithiated carbon in cyclic a-lithium enol ethers (Table 4.66). In terms of its a and / carbon-13 shifts, 2,7-dimethyloxepine is also a typical enol ether [420], Further, 2,6-dimethyl-4-pyrone [421] and flavone [422] display similiar shift values for the a, /1-enone substructure. 

Relatively few examples of photoreactions of seven-membered and larger heterocycles have been reported. The major products of irradiation of liquid oxepin are hex-5-en-l-ol and hexanal234 photodecomposition of cyclic ethers has, in general been shown to be largely dependent on ring size. Irradiation of the valence bond isomer (287) of hexakis(trifluoromethyl) oxepin gave the unexpectedly stable oxet (288) via a mixture of (Z)- and... 

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]. 

Arene oxide-oxepin systems have also been reported to undergo [2 + 4] or [4 + 6] pericyclic cycloaddition reactions with heterocyclic dienes like the tetrazine 279 and the triazine 280. 65 Thus 86 96 reacts with 279 and 280 to yield the dihydrooxepino [4,5-d] pyridazine 281 and the oxepino [4,5-c] pyridine 282, respectively, via a [2 + 4] cycloaddition as well as the phthalazine 283 and isoquinoline 284, respectively, probably via a [6 + 4] cycloaddition reaction. However, 157 gives only 285 and 286 arising from a [2 + 4] cycloaddition reaction. 

Rhodium(i)-catalyzed ene-allene carbocyclization strategy is suggested for the formation of seven-membered heterocycles, azepines and oxepines. In particular, treatment of an allenyl allyl ether with a catalytic quantity of chlorodi(carbonyl)rhodium dimer affords 4-alkylidene-5-alkyl-2,3,4,5-tetrahydrooxepines (Equation 28) in 40-55% yields <20040L2161>. 

This section follows the content of Section 9.02.8 in CHEC-II(1996) without repetition of data presented in the latter but refers to several papers omitted in CHEC-II(1996) along with new publications. Below are presented various synthetic methods, which are classified by the nature and size of the starting ring. Peculiar differences with CHEC-11(1996) should be marked (1) the absence of paragraphs devoted to formation of oxepine derivatives from four- and five-membered carbocycles because new syntheses of these kinds were not found in the literature (2) Sections 13.02.8.2.2, 13.02.8.2.5, and 13.02.8.2.6, which are new, appear concerning with formation of oxepine derivatives from four-, (other) seven-, and eight-membered heterocycles, respectively. 

The synthesis of medium-ring nitrogen heterocycles, such as azepines, azocines, and azonines, has been reviewed <1991T9131>. 1/7-Azepines 321 result from spontaneous valence-bond isomerization of azanorcaradienes 320 (Scheme 163), which are themselves made by reaction of arenes with nitrenes. Oxepins are prepared by an analogous method (323 324) the starting material is made from the dibromide 322 (Scheme 164) <1964AGE510>. 

Heating TV-ethoxycarbonylazepine with the electron-deficient diene (96) provided [2 + 4] adduct (97) and [6 -i- 4] adduct (90) in nearly equal quantities. Other examples of relatively low conversion [6 + 4] cycloadditions of substituted azepines and various dienes have been reported but are of little synthetic consequence due to low periselectivity and modest chemical yields. - Oxepin heterocycles display a range of reactions with dienes which are similar in scope to the azepine series and, as such, will not be dealt with specifically in this review. Other cyclic polyenes such as cyclooctatetraene are known to yield some [6 + 4] adducts when exposed to highly reactive diene species. For example, the potent electron-deficient diene 2,S-dimethoxycarbonyl-3,4-diphenylcyclopent ienone gives a modest amount of the corresponding [6 -I- 4] cycloadduct when reacted with cyclooctatetraene. ... 

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