Dioxepines and derivatives

Chlorine and bromine add normally to the double bond in (256) and the dibromo compound can be mono-dehydrobrominated using sodium methoxide in methanol to give a mixture of 5-bromo-4,7-dihydro-l,3-dioxepin and 5-bromo-4,5-dihydro-l,3-dioxepin (which is converted in situ to the 5-methoxy derivative). More interestingly it can be fully dehydrobrominated using HMPA at 140 °C to give the fully unsaturated 2H- 1,3-dioxepin (261) (76TL2113). This is the only known route to this compound. It gives a Diels-Alder adduct with 4-phenyl-l,2,4-triazoline-2,5-dione in 95% yield and on UV irradiation it isomerizes to (262). 

Several reports describe reactions on the attached rings of benzo-fused dioxepins and dithiepins. For example, biphenyl derivative 79 was prepared in a two-step procedure by halogenation of 130 with NaBr/oxone in aqueous acetone and subsequent substitution of the 131 with a methoxy group (Scheme 34) <2006T635>. 

However, it has turned out that there are a few synthetic methods having broad scope, that is, (a) for the synthesis of dioxepins and dithiepins (i) transacetalization of the corresponding diol or dithiol, respectively, with an open chain acetal (ii) treatment of the corresponding diol or dithiol with sodium borohydride and reaction of the resulting dianion with a gem-dihalogen derivative. The latter method is particularly useful for the synthesis of dioxepins and dithiepins unsubstituted in the 2-position (b) for the synthesis of 4,5-dihydro-l,3-dioxepins (i) metal- or base-catalyzed double-bond isomerization and (ii) Heck vinylation or arylation, respectively, for the synthesis of 6-substituted 4,5-dihydro-l,3-dioxepins. 

Perfluoro-2-methyl-2-pentene reacted with acyclic bifunctional nucleophiles such as 2-mercaptoethanol (89NKK1772) and ethylene glycol (86JAP61200983), in the presence of a base, to give 1,4-oxathiepin and dioxepin derivatives, respectively. Eight- and nine-membered heterocycles are obtained with 1,2-bifunctional benzenes such as salicyclic acid [81JFC(18)447]. 

The phosphine-phosphite BINAPHOS ligand was first used in the Rh-catalyzed asymmetric hydroformylation of heterocyclic olefins such as 2,5-dihydrofuran, 3-pyrroline derivatives, and 4,7-dihydro-1,3-dioxepin derivatives. It provided the optically active aldehydes as single products with enantioselectivity between 64-76% ee. In the hydroformylation of 2,5-di-... 

Dithiepins, particularly the 1,3 and 1,4-isomers have received more intensive study than dioxepins, particularly with regard to the possible aromatic character of the anions (279) and (289) derived from the fully unsaturated systems. The literature up to ca. 1970 has been reviewed <72HC(26)573>. 

Dihydro-1,3-dioxepins (298) are prepared by the reaction of m-butene-1,4-diols with aldehydes, and a similar route gave the dithia derivative (299) which was converted into the more unsaturated compound (301) via (300) (76TL1251). 

This chapter comprises an update on the chemistry of 1,2-dioxepines, 1,2-oxathiepines, and 1,2-dithiepines which appeared in Chapter 9.10 in CHEC-II(1996). It is evident that the structural nature, in terms of construction and/or stability of each of these seven-membered heterorings, which include a relatively weak O-O, O-S, or S-S bond, lies behind the paucity of publications in this area. However, the literature on the effective antimalarial artemisinin 1, a remarkably stable endoperoxide, and especially its derivatives more than make up for this deficiency. 

The relative thermodynamic stabilities of 4,7-dihydro- and 4,5-dihydro-l,3-dioxepins as well as a number of their 2-subtituted derivatives have been determined by base-catalyzed chemical equilibration in dimethyl sulfoxide (DMSO) <1999STC295>. 

The conformation of cyclopropanoaziridines has been studied by 111 and 13C NMR spectroscopy several other cyclopropane derivatives, derived from dioxepins, have also been described <2003HCA2779>. 

Dioxepins derived from 1,4-diols and a-phenylsulfonylacetaldehyde diethyl acetal have proved to be robust protection groups for 1,4-diols under a variety of reaction conditions. They are stable to 60% AcOH, 6M HC1, and 0.1 M H2SC>4, and they resist /3-elimination by reaction with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Cleavage was achieved with either lithium amide in liquid ammonia at —33 °C or -butyllithium at 35 °C (Scheme 24) <2003SC895>. 

Another useful procedure for the synthesis of dioxepins, oxathiepins, as well as dithiepins under basic conditions involves deprotonation of a diol or dithiol precursor and treatment of the resulting anion with a gdihalo compound, as demonstrated with the synthesis of the TADDOL-derived oxathiepin 64 <1991SL844> and biaryl derivative 132 <2005TL7291> (Scheme 62) ... 

The Heck reaction of 4,7-dihydro-l,3-dioxepins has found further applications in the total synthesis of naturally occurring compounds. For example, 4,5-dihydro-l,3-dioxepin 241 was prepared as an intermediate in the synthesis of Brefeldin A <1999JOC3800>, and the /fV/-butyl derivative of 106 in the synthesis of (-l-)-curcuquinone and (—)-curcuhydroquinone (Scheme 72) <2003ARK232>. 

Dioxepane 55 has found application in the manufacturing of vitamin B6. Cycloadduct 55 was obtained by Diels-Alder reaction of 2-isopropyl-4,7-dihydro-l,3-dioxepin with 4-methyl-5-ethyloxy-l,3-oxazol (see Section 13.11.6.2), and the resulting adduct was rearranged in the presence of an acid to give pyridoxol derivative 268 <2004DE10261271A1, 2005W0049618A1> (Scheme 83). 

A serendipitous synthesis of the l,4-dioxepin-5-one derivative 228 has been reported based on acid chloride formation from the acid 227, followed by a ring opening and ring closing sequence on exposure of the acid chloride to 48% HBr solution [01TL2305]. 

The chiral substituted 1,3-dioxepine derivative 231 has been prepared in 96% ee (50% conversion) by an asymmetric Heck reaction with the alkene 229 and the aryl triflate 230 [01OL161 ]. 

Arylation of the 4,7-dihydro-l,3-dioxepin system 68 (easily derived from cis-2-butene-l,4-diol), once again using the triflate, was reported by Shibasaki et al. in 1994 [57]. The reaction is significant in that the resulting enol ethers are easily converted (by hydrolysis and then oxidation of the intermediate lactol) to chiral P-aryl-y-butyrolactones 70, which are themselves useful synthetic intermediates (Scheme 18) [58]. Also noteworthy is the important role played by added molecular sieves (MS), which enhance both chemical yield and ee. This was the first time that such an effect had been noted for the AHR. 

Amide Derivatives of MA-1,3-Dioxepin Copolymers. ID-MA copolymer (4.0g) was combined with 30ml aniline and stirred under nitrogen for 48 hr. at room temperature. After 24 hr. all the dispersed copolymer had dissolved in the aniline solution. The amide copolymer was precipitated with diethyl ether. The copolymer was purified by dissolving in methanol/acetone (50/50, v/v), reprecipitation from diethyl ether and drying in vacuo for 24 hr. at 58°C. 

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