2.3- Dihydro-5/7-1,4-dioxepins

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-... 

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). 

The 6,7-dihydro-5/f -1,4-dioxepin (266) has been prepared (54CR(38)982). and more recently it has been shown that the 2,3-dihydro-5jF/-l,4-dioxepins (263) and (265) can be produced from 1,4-dioxine-halocarbene adducts (264), either by heating under reflux in xylene or by treatment with bases. The allylic chlorine atom in (263) is readily substituted by alkoxide or cyanide ions (77ZC331, 76UKZ968). Saturated rings of type (267) have been prepared by the treatment of cyclic acetals of ethane-1,2-diol with vinyl ethers in the presence of boron trifluoride, and l,4-dioxepan-5-one (268) has been prepared by the reaction of bromoform and silver nitrate with aqueous dioxane (60AG415). 

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). 

One general method for the preparation of 6,7-dihydro-l,4-dioxepins of type (362) involves ring expansion thus, treatment of 2-(methoxymethyl)-l,3-dioxane (361) with dodecylbenzenesulfonic acid at 250°C and simultaneous distillation gave (362) with 69% conversion and 84% selectivity... 

In contrast, the carboxidation of 2,5-dihydrofuran (entry 2) and 4,7-dihydro-l,3-dioxepin (entry 4), having a more distant location of the double bonds, proceeds with minor cleavage, leading in both cases to formation of the corresponding ketones with 94% selectivity. 

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 addition of chlorine and bromine or the epoxidation of 4,7-dihydro-l,3-dioxepins 46 has already been described in CHEC-II(1996). Treatment of 46c with iodobenzene diacetate and A-aminosuccinimide in MeCN yielded a mixture of exo- and OT -A-amino-substituted aziridinodioxepanes 22c (Scheme 1) <2005AXC705> (cf. Section 13.11.3.2). The diastereomeric mixture was easily separated by column purification of the crude reaction product. 

Dihydro-l,3-dioxepins 47 have been oxidized with w-chloroperbenzoic acid to give 4,5-dihydroxylated products. The product formation depends on the solvent used for oxidation. In dichloromethane (DCM), 4-acyloxy-5-hydroxydioxepanes 21 were formed whereas, the same reaction in MeOH afforded 5-hydroxy 4-methoxydioxepanes 48 (Scheme 2) <2001AGE177>. 

Copper-catalyzed cyclopropanation of 4,7-dihydro-l,3-dioxepin 46a with ethyl diazoacetate gave cyclopropanodiox-epane 49, as the only product. The product formation of cyclopropanation with dimethyl diazomalonate (dmdm) catalyzed by copper(n) acetylacetonate depends on the substitution pattern of the dioxepin (Scheme 3) <2000HCA966>. 

Dihydro-l,3-dioxepin 47b reacted with dimethyl diazomalonate in a double [3+2] cycloaddition reaction to give furofuran derivative 54 as a mixture of stereoisomers (Scheme 4) <2000HCA966>. 

The Diels-Alder reaction of 2-isopropyl-4,7-dihydro-l,3-dioxepin 46 and 5-ethyloxy-4-methyl-l,3-oxazol affords adduct 55 (Scheme 5) <2005W0049618A1>. 

The noncatalytic oxidation of 4,7-dihydro-l,3-dioxepin 46a with nitrous oxide in liquid phase at 220 °C produces 1,3-dioxepan-5-one however, the conversion is very slow <2004ASC268>. 

In the synthesis of the monocyclic bisabolene-type sesquiterpenoids (-f)-curcuquinone and (—)-curcuhydro-quinone, 1,3-diol 107 was obtained by ozonolysis of 4,5-dihydro-l,3-dioxepin 106 (obtained by Heck reaction, see Section 13.11.10) and reductive workup (Scheme 25) <2003ARK232>. 

Synthesis of acetonides can also be performed using 2-methoxypropene instead of 2,2-dimethoxypropane <20050L5011> however, 4,5-dihydro-l,3-dioxepins, such as 216 (Scheme 61), can only be obtained by direct acetalization or transacetalization with special substrates. 

Similarly, 2-phenylsulfinylmethyl-substituted 4,7-dihydro-l,3-dioxepin was prepared by the reaction of r-butene-2,3-diol with 2.2equiv of sodium hydride and l-phenylsufinyl-2-phenylsulfanylethylene <2005TL1035>. 

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>. 

Hydroxy-4,5-dihydro-l,3-dioxepin 81 (cf. section 7 of Chapter 13.11) was obtained by ring opening of epoxy-dioxepane 128 with lithium amide (Scheme 75) <2004RJOC1876>. 

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. 

Dihydro-l,3-dioxepins were used as chiral building blocks <2001AG(E)177> and substrates for the synthesis of naturally occurring compounds <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). 

Treatment of 1,3-dioxalanes 20 with thionyl chloride and then 48% hydrobromic acid gave 7-(perfluoroalkyl)-2,3-dihydro-57/-l,4-dioxepin-5-ones, 50-95% yield (Equation 8) <2001TL2305>. 

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