4,7-dihydro-l,3-dioxepines

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). 

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 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. 

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>. 

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>. 

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>. 

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 nickel catalyst containing Me-DuPhos has been shown to be effective in the enantioselective isomerization of 4,7-dihydro-l,3-dioxepins 72.71 Diastereoselective oxidation of the resulting 4,5-dihydro-l,3-dioxepins 73 allowed access to a range of C-4 chiral synthons (Scheme 13.26). 

The primary adducts (156) and (157) of oxazoles with alkenes and alkynes, respectively, are usually too unstable to be isolated. An exception is compound (158), obtained from 5-ethoxy-4-methyloxazole and 4,7-dihydro-l,3-dioxepin, which has been separated into its endo and exo components. If the dienophile is unsymmetrical the cycloaddition can take place in two senses. This is usually the case in the reactions of oxazoles with monosubstituted alkynes with alkenes on the other hand, regioselectivity is observed. Attempts to rationalize the orientation of the major adducts by the use of various MO indices, such as 7r-electron densities or localization energies and by Frontier MO theory (80KGS1255) have not been uniformly successful. A general rule for the reactions of alkyl- and alkoxy-substituted oxazoles is that in the adducts the more electronegative substituent R4 of the dienophile occupies the position shown in formula (156). The primary adducts undergo a spontaneous decomposition, whose outcome depends on the nature of the groups R and on whether alkenes or alkynes have been employed. 

Dihydro-l,3-dioxepins 422 are prepared by the reaction of m-butene-l,4-diols with aldehydes, and a similar route gives the dithia derivative 423 which is converted into the more unsaturated compound 425 via 424 (Scheme 196)... 

BF3 Et20 is used for a stereospecific 1,2-alkyl migration to form trau5-2-alkyltetra-hydrofuran-3-carbaldehydes from 4,5-dihydrodioxepins (Eq. 50), which are obtained by isomerization of 4,7-dihydro-l,3-dioxepins [95]. Similarly, a-alkyl-/3-alkoxyalde-hydes can be prepared from 1-alkenyl alkyl acetals by a 1,3-migration using BF3 Et20 as catalyst [96]. syn Products are obtained from ( )-l-alkenyl alkyl acetals and anti products from (Z)-acetals. 

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. 

As part of an ongoing program to prepare and study new, water soluble polymers, attention was focused on the possible radical copolymerization of 4,7-dihydro-l,3-dioxepins with maleic anhydride (MA) and maleimides. 

A wide variety of 4,7-dihydro-l,3-dioxepins or l,3-dioxep-5-enes are known (1, 2). These cyclic acetal or ketal compounds are conveniently prepared by the acid catalyzed reaction of cis-2-1 Current address University of Wisconsin, Madison, WI53706. 

Results and Discussion. It is claimed in the patent literature that 1,3-dioxepins will copolymerize with a variety of vinyl monomers (4,29) and function well as chain transfer agents (29) in the polymerization of vinyl monomers. In view of these reports and prior to any copolymerization studies, we wished to know if any of the 4,7-dihydro-l,3-dioxepins prepared (Table I) would undergo free-radical initiated homopolymerization. Free-radical polymerization of IA-IE were not observed. Using IA, Yokoyama and Hall (10) confirmed these results. 

Since 4,7-dihydro-l,3-dioxepin (IA) is both the simplest and one of the more easily prepared 1,3-dioxepin monomers (Table I), copolymerization of equimolar mixtures of IA-MA were first examined under a variety of conditions (Table II). As shown, yields of 1 1 alternating IA-MA copolymer are highly dependent upon polymerization conditions, with highest conversions obtained in 1,2-dichloroethane solvent. Also, incremental or controlled addition of initiator improves yields of copolymer. Using DCE solvent, the copolymers precipitated during polymerization. Copolymerization without added initiator was not observed. 

A sample of poly (2,2-diraethyl-4,7-dihydro-l,3-dioxepin-alt-maleic anhydride) polymers was fractionated and briefly examined for antiviral properties (31). The copolymer was fractionated through Amicon filters into a 1,000-10,000 and 10,000-30,000 molecular weight cuts. Both molecular weight fractions were examined for effect against mice inoculated (ip) with 106 Ehrlich Ascites tumor cells. Five days after inoculation the animals were sacrificed and total peritoneal exudate cells were counted with a hemo-cytometer. Under these conditions, Ottenbrite (31) showed that the 1,000-10,000 molecular weight fraction of the ID-MA copolymer was as effective as Pyran (control in experiment) for control of Ehrlich Ascites tumor cells. Pyran, the copolymer of divinyl ether-MA is a well known antitumor agent (32) and interferon inducer (33). 

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