Dioxepanes, substituted

A high level of activity continues in connection with the synthesis of antimalarial artemisinin analogues and congeners, in which the 1,2-dioxepane moiety is embedded. Recent examples include the syntheses of various 10-substituted deoxoartemisinins of type 123 (eg. R1 = Cl COMe) from dihydroartemisinin acetate, and of type 124 (eg. R2 = a-OH, R3 = Me), from Grignard reagent addition to 10-(2-oxoethyl)deoxoartemisinin . 

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). 

Ozonolysis of a substituted ene function (as part of acyclic or cyclic structure) has been used extensively in the preparation of 1,2-dioxepane derivatives. A classic example of this reaction was the ozonolysis of ene 64 to yield artemisinin 1 in 35% yield (Equation 13) <1992JA974, 1997BML2357, 2002JME4321, 1996JME4149, 1996JME2900>. 

The reaction of 6-methylene-l,3-dioxepanes 89 with trimethylsilyl trifluoromethanesulfonate in the presence of lithium diisopropylamide gave 4-formyltetrahydropyrans 90 as ring-contraction products in 29-77% yield. In the case of 4-phenyl-substituted substrate 89a, trimethylsilyl enol ether 91 was isolated as an intermediate (Scheme 17) <2005BCJ2209>. 

Rearrangement of 4-alkyloxy- 48 and 4-acyloxy-l,3-dioxepanes 21 in the presence of an acid depends on the solvent. The rearrangement in DCM gave 2-substituted l,3-dioxane-4-carbaldehydes whereas reaction in aqueous solution afforded tetrahydrofuran derivatives 93. Crossover experiments indicated that the rearrangement in aqueous solution probably proceeds via 3-deoxyglycerotetrose, which immediately reacts with the carbonyl compound to give 93b and 93d (Scheme 18) <2001AGE177>. 

N-(o-, m-, or />-)hydroxylaminobenzenesulfonyl dioxepanoaziridines <1996US5545659> and O-substituted 6-sulfon-amido-l,3-dioxepan-5-ols <1997US5635529> have found application because of their hypoglycemic activity. 

Mulzer et al. have extended the applicability of the insertion reaction of ketene into an acetal, to that of a substituted ketene into a 1,3-dioxalane to provide an elegant synthesis of 6,6-dichloro-l,4-dioxepan-5-ones (Equation 13) <1996AGE1970>. 

Polymerizability of substituted 7-membered cyclic acetals 1,3-dioxepanes (6-mem-bered 1,3-dioxanes do not polymerize) was also studied by Okada 52,53). Major information is gathered in Table 2.9. 

Table 2.9. Thermodynamic parameters in the polymerization of substituted 1,3-dioxepanes 52-53)...

The bulk polymerization of 4-methyl-1,3-dioxepane at 0 °C yields 60% polymer. Further substitution decreases polymerizability as with 1,3-dioxolanes. 2,4-Dimethyl-1,3-dioxepane gives oligomers in limited yield, the 2,2-dimethyl-derivative dimerizes and the 4,4-dimethyl derivative does not polymerize at all53). 

Treatment with phosphorus pentachloride results in the formation of 4-chlorobutyl acetate <73JOCll73>. 4-Bromobutyl esters are also produced by bromination of 1,3-dioxepane and 2-mono-substituted 1,3-dioxepanes with Af -bromosuccinimide at 70°C. Bromination in the side chain occurs only at lower temperatures, or when both 2-positions are substituted <81KGS174>. Use of dioxane-dibromide in dioxane as brominating agent at ambient temperatures predominantly leads to a-bromoalkyl derivatives <77DOK(237)338,78KGS131>. 

Treatment of 2,2-dimethyl-1,3-dioxepane with carboxylic acids results in the formation of tetra-hydrofuran and acetone <6UOC4762>. Acid-catalyzed hydrolysis of methyl-substituted 2,2-diphenyl-... 

Diphenylphosphane-substituted 1,3-dioxepane (12 X = PPh2) has been applied in the synthesis of fluxional transition metal complexes with mixed oxygen-phosphane ligands <92ICA237,93CB1317, 93IC1266, 94ICA165). 

In comparison to the fully saturated 1,3-dioxepane system, the number of possible conformations for 4,7-dihydro-1,3-dioxepins is reduced because of the sp hybridization at carbons 5 and 6 <76BSF307). There are two chair, two twist and two boat conformations. NMR spectroscopic data indicate a rapid equilibrium between the chair and the twist conformations. It has also been shown that the conformational ratio strongly depends on the substitution pattern in positions 2, 4, and 7 <65MI 911-01,75JOC450,86ZOB144,95HCA2I48). The most Stable Conformation of benzodioxepins was determined by low-temperature NMR measurements <81CJC2283). Evidence for a twist-chair con-... 

Two types of benzoannelated ethers containing a 1,4-dioxepane moiety are known 3,4-dihydro-2//-l,5-benzodioxepin (21), and 2,3-dihydro-5//-l,4-dioxepin (22). 3,4-Dihydro-2/f-l,5-benzo-dioxepin (21) can be prepared either from (20) or (23). Derivative (25) has been obtained by the reaction of 2-hydroxy-2,3-dihydro-2-phenyl-l,4-benzodioxin (24) with phenacylbromide <87UKZ614>, and compounds (26) were isolated as by-products together with isomeric 2-substituted 2,3-dihydro-2-hydroxymethyl-l,4-benzodioxins from the reaction of a-(2-hydroxyphenoxy)-alkylketones and dimethylsulfoxonium methylide <88JHC943>. 

Iodomethyl-substituted 1,4-dioxepan-2-ones (106) were obtained by iodolactonization of 3-oxa-6-heptenoic acids (104) with bis(5yw-collidine)iodine(I) hexafluorophosphate (105), as the transfer reagent. This reaction occurs regioselectively via an exo-mode cyclization <94JOC59i2>. 

Of the cationically-polymerizable cyclic acetals, 1-3-dioxolan has received the most attention. By means of an ion-trapping technique, quantitative measurements of the concentration of active centres have been made and correlated with initiator incorporation to confirm the living characteristics of the linear polymers under certain conditions. The oxycarbenium ion nature of these propagating centres has been verified by C-n.m.r. spectroscopy. Methyl substitution alters the polymerizability of the homologous 1,3-dioxepanes significantly and steric hindrance in the initiator can influence both the homopolymerization and copolymerization of cyclic acetals. ... 

By reacting 1,4-butane diol with paraformaldehyde in the presence of sulfuric acid at 150-180" , the seven-membered 1,3-dioxepane is prepared. With other aldehydes, homologous 2-alkyl-substituted 1,3-dioxepanes have also been prepared using a cationic ion exchange resin instead of sulfuric acid. This latter technique was introduced by Astle [42]. The dioxepanes have been converted to polymers in methylene dichloride or in 1,2-dichloro-ethylene. The initiator used was boron trifluoride etherate the reaction temperatures ranged from -10° to +10°. The reactions were carried out under anhydrous conditions by techniques suitable for reaction kinetics studies. The work indicated that, at least for this class of compounds, the polymerization propagation step involves linear alkoxycarbenium ions [47]. 

Many of these heterocydes are commerdally available. They arise from petroleum as source, except LA. Methyl-substituted seven-membered ring carbonates (7CCs), namely 4-methyl-and 5-methyl-l,3-dioxepan-2-one (R-Me7CC and p-Me7CC), have been synthesized by cydization of the corresponding a,[Pg.71]

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