1,4-Benzodioxane

Miscellaneous OC-Substituted Peroxides. 3-Aryl-3-(/ i alkylperoxy)-phthaHdes (12) are prepared from the corresponding 3-chlorophthaHdes and alkyl hydroperoxide (156). 2-Methyl-2-(/ f2 -alkylperoxy)-l,3-benzodioxan-4-ones (13) are obtained from 0-acetylsaHcyloyl chloride and alkyl hydroperoxides (157). Trisubstituted 2-(/ f2 -alkylperoxy)-l,3-dioxolan-4-ones (14) are synthesized from stericaHy favored a-acyloxy acid chlorides and alkyl hydroperoxides (158). 

In addition to the normal methylene linkage formation involved in polymerization with both resoles and novolaes, other, usually less desirable, eondensation by-products are also seen in novolac synthesis. Among these are benzodioxanes and dibenzyl ethers. The reaction pH has significant effect on the relative amounts produced. Fig. 15 shows typical structures for these by-products. When such byproducts are present, the meaning of the molar ratio changes and variability with respect to molecular weight development, glass transition point, and solubility may be seen. They also lead to poor raw material utilization. 

Reaction of pyroc techol with epichlorohydrin in the presence of base affords the benzodioxan derivative, 136, (The reaction may well involve initial displacement of halogen by phenoxide followed by opening of the oxirane by the anion from the second phenolic group.) Treatment of the alcohol with thio-nyl chloride gives the corresponding chloro compound (137). Displacement of halogen by means of diethylamine affords piper-oxan (138), a compound with a-sympathetic blocking activity. 

An imidazole derivative which is also a hypotensive agent by virtue of adrenergic a-2-receptor blockade is imiloxan (75). Its synthe.sis begins by conversion of 2-cyanomethyl-1,4-benzodioxane (72) to its iminosMhylether with anhydrous HC in clhanol (73). Reaction of the latter with aminoacetaldehyde diethylacetal and subsequent acid treatment produces the imidazole ring (74). Alkylation of 74 with ethyl iodide mediated by sodium hydride completes the synthesis [251. 

Azaloxan (12) is an antidepressant agent. Its synthesis can be accomplished starting with the reaction of catechol (7) and 3,4-dibromobutyronitrile (obtained by addition of bromine to the olefin) to give l,4-benzodioxan-2-ylacetonitrile (8). A series of functional group transformations ensues [hydrolysis to the acid (9), reduction to the alcohol (10) and conversion to a tosylate (11)] culminating in an SN-2 displacement reaction on tosylate 11 with l-(4-piperidinyl)-2-imidazolidi-none to give azaloxan (12) [3]. 

Approximately 4-6 wt % phenol can typically be recovered following novolac reactions. Free phenol can be removed by washing with water repeatedly. The recovered phenolic components may contain 1,3-benzodioxane, probably derived from benzyl hemiformals (Fig. 1.1) ... 

Wefero-Dlels-Alder reactions of 3,5-di-fe/-f-butyl-o-benzoquinone with acyclic dienes novel synthesis of 1,4-benzodioxanes [135]... 

Hie Pd-catalysed coupling of aiyl and heteroaryl halides with 2-hydroxyphenyl 2-propynyl ethers leads to (Z)-2-arylidene-l,4-benzodioxanes <96CC1067>. 

The reaction between o-quinones and electron rich dienes leads to benzodioxanes. It is proposed that an initial HDA followed by a [3,3] sigmatropic rearrangement account for the stereochemistry of the products <96JCS(P1)443>. 

Similar temperature effect using other racemic alcohols such as 2-hydroxymethyl-1,4-benzodioxane (4), 2-phenylpropanol (5), and 1-cyclohexylethanol (6) was also observed as shown in Fig. 8, obeying Equation 7. These results suggest that the temperature effect is widely applicable regardless of primary or secondary alcohols and an origin of lipase. 

Ralph, J. Lapierre, C. Lu, F. Marita, J. M. Pilate, G. Van Doorsselaere, J. Boerjan, W. Jouanin, L. NMR evidence for benzodioxane structures resulting from incorporation of 5-hydroxyconiferyl alcohol into lignins of O-methyl-transferase-deficient poplars. j. Agric. Food Chem. 2001, 49, 86-91. 

Morreel, K. Ralph, J. Lu, F Goeminne, G. Busson, R. Herdewijn, P. Goeman, J. L. Van der Eycken, J. Boeijan, W. Messens, E. Phenolic profiling of caffeic acid O-methyltransferase-dehcient poplar reveals novel benzodioxane oligolignols. Plant Physiol. 2004, 136, 4023 1036. 

In the reactions which we have just discussed, the initial reaction involves only the carbonyl group. We therefore looked next at reactions of tetrachlorobenzyne with simpler aldehydes. It is noteworthy that o-carboxybenzenediazonium salts are known to yield 1,3-benzodioxan-4-ones, for example, (129) with carbonyl compounds 166>, and 2,2-diphenyl-3,l-benzo-oxathian-4-one (130) with thiobenzophenone 167>. These products are presumably formed via reactions with the intermediate (128). 

The aprotic diazotisation of tetrachloroanthranilic acid in the presence of benzaldehyde or />-methoxybenzaldehyde results in the formation of the 1,3-benzodioxan derivatives (131, R = Ph) and (131, R = >-C gH 4-OMe) respectively 155). The absence of products analogous to (129) in these reactions suggests that the formation of the compounds (131) do involve tetrachlorobenzyne. Some indication of the mechanism of these reactions was given by the fact that no analogous adduct has been isolated in attempted reactions of tetrachlorobenzyne with p-nitrobenzaldehyde. However, in the presence of acetone we obtained a low yield of the compound (132). 

Commensurately with the development of various catalyst systems, the Pd-catalyzed G-O cross-coupling has found a number of synthetic applications. Examples include the syntheses of the protein kinase G (PKC) activator (+)-decursin,104 the natural product heliannuol E,105 a chiral 2-methyl chroman,106 and a series of aryloxy and alkoxy porphyrins.107 The Buchwald-Hartwig coupling has also been utilized in the preparation of a heterocycle library.108 Intramolecular O-arylation has also been achieved in the reactions of enolates with aryl halides leading to benzofur-ans.109,110 Finally, a double cross-coupling between an 0-dibromobenzene and a glycol has also been applied for the preparation of benzodioxanes (Equation (16)).1... 

This type of reactivity has been exploited for the preparation of 1,4-benzodioxanes from catechols and propargylic carbonates. Using 2,2 -bis(diphenylphosphino)-l,T-binapthyl (BINAP), this process has been rendered asymmetric with ee s up to 97% (Equation (68)).254,255... 

Finally, very recently Pallavicini et al., in continuation of a previous study on ortho-monosubstituted compounds, designed and synthesized a series of 2-[(2-phenox-yethyl) aminomethyl]-l,4-benzodioxanes ortho-disubstituted at the phenoxy moiety [99]. The disubstituted analogues were tested for their binding affinities at the three oq-AR subtypes and for the 5-HT1A-R. The affinity values of the new compounds were compared with those of the enantiomers of the 2,6-dimethoxyphenoxy analogue, the well-known oq-AR antagonist WB-4101 (Scheme 8.1), and of the ortho-monosubstituted derivatives. The results suggested some distinctive aspects in the interaction of the phenoxy moiety of monosubstituted and disubstituted compounds with the cqa-AR and the 5-HTiA receptors. A classical (Hansch) QSAR analysis was applied to the whole... 

M., Fanelli, F. and De Benedetti, P.G. (1992) Molecular modeling and quantitative structure-activity relationship analysis using theoretical descriptors of 1,4-benzodioxan (WB-4101) related compounds al-adrenergic antagonists. Journal of Molecular Structure (Theochem), 276, 327-340. 

Diamino-6,7-dimethoxyquinazo-lines. 1.2-[4-(l,4-Benzodioxan-2-ylcarbonyl)piperazin-l-yl] derivatives as alpha 1-adrenoceptor antagonists and antihypertensive agents. Journal of Medicinal Chemistry, 30, 49-57. 

Quaglia, W., Pigini, M., Giannella, M. and Melchiorre, C. (1990) 3-Phenyl analogues of 2-[[[2-(2,6-dimethoxyphenoxy)ethyl]amino]-methyl]-l, 4-benzodioxan (WB 4101) as highly selective alpha 1-adrenoceptor antagonists. Journal of Medicinal Chemistry, 33, 2946-2948. 

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