Benzoxepine ring

An alternative method for benzoxepine ring assembly uses the formation of cyclic ethers. Thus, benzoxepino[4,3-f>]indole 130 can be synthesized by the treatment of the keto-alcohol 129 with hot alcoholic base to produce the product in 90% yield as a result of intramolecular nucleophilic substitution (Equation (19) (1993AX(C)2126)). 

Benzazepine and benzoxepine ring systems showed high CNS activity and their syntheses have been reported [142]. The key step in this synthesis exploited an alternative route to form oxepine or thiepine ring systems 61 via a Pd-catalyzed cyclo-amination of 60. Overall, the best yields were achieved with Pd2(dba)3 as the palladium source, P(Z-Bu)3 as the ligand, Z-BuONa alone or with K2CO3, in toluene [142]. 

However, the presence of a fused benzene ring was found to hmit the scope of this type of ring expansion severely. Thus the dichloro-carbene adducts of both 2H- (33) and 4H-chromen (34) failed to rearrange to 2,3-benzoxepines (35) on heating. Although some... 

The 2a,7b-dihydrocyclobuta[7>]benzofuran structure, obtained by addition of activated acetylenes to benzofurans (see Houben-Weyl, Vol.E6b, p 148), isomerizes thermally to a 1-benz-oxepin182 184 185 which reacts further to 1-naphthol derivatives at higher temperature182,185 (see Section 1.2 ). Under photochemical conditions, the 1-benzoxepins undergo ring contraction to the starting material.182 184... 

Benzoxepin forms complexes with tricarbonylchromium, -tungsten and -molybdenum. All three metals, however, use the 71-system of the phenyl ring for complexation.255... 

Eberbach has shown that pyrolysis of the system 39, in which both A and B represent benzene rings, the product is the stable dihydrodibenzo[c,e]oxepine 40, (A,B = benzo), in which the intermediate ylide undegoes a 1,7-electrocyclisation followed by a [1,5] H shift (Scheme 9) <85CB4035>. This work has now been extended by Sharp to include systems where B is a thiophene or pyridine, offering a route to the corresponding thieno- and pyrido-benzoxepines <96JCS(P1)515>. 

The synthesis of these rings involves annulation of the furan ring onto the preformed benzoxepine core or intramolecular oxepine C-C bond formation of the furan precursors. Thus, 2-methyldibenzo[ 7,/]furo[2,3-d]oxepines 148 (R = H, Cl)... 

Electrophilic substitutions of rings with a single N-nucleophilic site proceed smoothly. Thus, indolo benzazepine 36a, protected on the indole ring, and benzoxepine 36c are easily methylated on the benzazepine nitrogen (Scheme 79 (1991JHC379)). 

Benzoannelation of the oxepane ring system leads to an increase in the barrier to ring inversion. Thus variable temperature NMR spectra on l,2,4,5-tetrahydro-3-benzoxepin (2) suggested that a chair conformation was preferred with a barrier to ring inversion of ca. 39.7 kJ mol"1. 

The predominant initial bond fission in 2,3,4,5-tetrahydro-l-benzoxepin (6) was again at the C—O bond with ring contraction steps occurring to yield five- or six-membered ring products (68OMS(l)403, 730MS(7)479>. 

Similarly, the fusion of an aromatic ring to the oxepin-benzene oxide system was found to drive the equilibrium toward extremes in either direction. The calculated resonance energies for oxepins (26), (27) and (28) were 4.81, 78.46 and 81.72 kJ mol-1 respectively (70T4269). These calculated values concur with experimental observations since oxepins (27) and (28) have been synthesized and are relatively stable compounds. The formation of 2-benzoxepin (26) from naphthalene 1,2-oxide would involve a considerable loss in resonance energy to the system and has not been detected spectroscopically (67AG(E)385). 

This reaction is directly analogous to that found with 1-benzoxepin and the valence tautomeric cyclobutene product obtained from (46) and was formed by a concerted disrota-tory ring closure mechanism. 

Benzoxepins are frequently synthesized by cyclization of alkyl aryl or diaryl ether precursors. An intramolecular Wittig reaction (equation 48) is used to provide the ring closure step in the synthesis of 1-benzoxepin (28) (68JOC2591). An internuclear cyclization reaction of an aromatic sulfonyl chloride (equation 49) occurred upon heating (250 °C) in the presence of a copper chloride catalyst to yield tribenz[6,d,/]oxepin (175). The analogous thiepin (see equation 71) may also be synthesized by this route (65T1299). 

The acid-catalyzed ring expansion of a spiroepoxide (equation 58) also yielded only the keto tautomer of a 1-benzoxepin. The enolic form of the oxepin in this example however was stabilized by conversion to the diacetate (194) (69CB205). 

The palladium catalysed sequential alkylation-alkenylation of 5-iodoquinoline leads to the formation of the quinolooxepin ring system (5.20.), The process, closely related to the Catellani reaction,19 runs through an ort/zo-alkylation - Heck reaction sequence. The preparation of a series of benzoxepines has also been achieved in this manner, starting from such iodobenzene derivatives, where one of the or/7 o-positions was blocked by substitution.20... 

Z)-Styryloxiranes 154 undergo a thermal ring expansion reaction to give carbonyl ylides 155, which cyclize to 2,7-dihydro-3,4-benzoxepines 156 (Scheme 47) (79TL4049 85CB4035). 

Chromanone and its isomer isochroman-4-one (623) add ethyl diazoacetate at the carbonyl group and the resulting compound undergoes ring enlargement on treatment with mineral acid. The benzoxepin-4(3H)-one (624) is obtained on heating with acid (79JCR(S)142). 

A further development of this route (71JOC4028), involving the cyclization of 3-(o-formylphenoxy)propyltriphenylphosphonium salts in methanol, has led to high yields of 2-methylchromene. In the detailed mechanism which has been proposed, an o-quinoneallide is considered to arise by the ring opening of an initially formed benzoxepin derivative. Indeed, 2,3-dihydro-1-benzoxepin is the major product of the reaction in aprotic solvents. 

The formation of a benzoxepin derivative during the synthesis of chromenes from phosphonium salts has been postulated (see p. 749). In keeping with this idea, chromenes are produced by ring opening of benzoxepin (121) with methoxide ion in DMF (69C108). The initial product, a butadienylphenol (122), undergoes a [l,7]-hydrogen shift to the quinoneallide. 

Examples of 47i electrocyclization and related ring openings in oxygen-and sulfur-containing heterocycles have been widely reported. The effect of substituents on the ease of photocyclization of 1-benzoxepins (1) to cyclo-buta[b]-l-benzofurans (2) has been studied.3 1,3-Dioxepin (3) is readily converted to 2,4-dioxabicyclo[3.2.0]hept-6-ene (4) on irradiation in diethyl... 

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