Benzodioxans

The majority of the small number of biologically active compounds based on a fused ring system that includes two oxygen atoms consist of 1,4-benzodioxans. All but one 

A rather simpler compound includes both a benzodioxan nucleus and the imidazoline function associated with a-adrenergic agonists such as clonidine. As in the standard approach for preparing imidazolines, the treatment of nitrile (60-1) with alcoholic hydrogen chloride leads to the iminoether (60-2). Reaction of that intermediate with ethylenediamine then affords idazoxin (60-3) [70], a compound that interacts with a-adrenergic receptors. 

Attachment of a base-bearing side chain to the carbocyclic ring of a benzodioxan gives another compound that acts as an a-adrenergic blocker. Mannich reaction of the methyl ketone in (61-2), obtainable by acetylation of the benzodioxan proper (61-1), with phenylpyrrolidine (61-3) and formaldehyde leads directly to proroxan (61-4) [71]. 

The benzodioxan ring also serves as the aromatic moiety for one of the ubiquitous analogues of the spirone anxiolytic agents discussed in Chapter 9. In the absence of a specific reference, the requisite intermediate (62-1) could be obtained by reducing the cyano group in nitrile (60-1) with lithium aluminum hydride. Alkylation with the spirone side chain chloride (62-2) would then afford binospirone (62-3). 

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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. 

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

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. 

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... 

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. 

Benzodioxan [493-09-4] Daphnla pulex EC50 (48-h) 1.46 Passino and Smith, 1987... 

The affinity of phenoxyethylamines for adrenergic receptor sites is enhanced by cyclization to analogous aminomethyl-1,4-benzodioxans such as pjperoxan (XLVI, R R = (CHjIs) which block a-receptors [240]. 

Beckmann rearrangement, 157 Bemidone, 305 Bemigride, 258 Benactizine, 93 Benadryl , 41 Bendroflumethiazide, 358 Benzamphetamine, 70 Benzestrol, 103 Benziodarone, 313, 314 Benzocaine, 9 1,4-Benzodioxans, 352 Benzguinamide, 350 Benzydamine, 323 Benzylpenicillin, 408, 409, 410 Bergstrom, Sune, 24 Beta eucaine, 9 Betamethosone, 198 Bethanidine, 55 Bhang, 394... 

The hydrophobicity of ionic liquids was found to be particularly beneficial for lipase PS-C-catalyzed transesterification of 2-hydroxymethyl-1,4-benzodioxane in the presence of vinyl acetate (277). The hydrophobic [BMIMJPFg functioned as a better promotional medium than methylene chloride and hydrophilic [BMIM]BF4, with either supported or unsupported enzyme for the catalytic transesterifications. The ionic liquid not only acted as a medium but also as a permanent host for the enzymes, so that the enzyme-ionic liquid system could be recycled several times without substantial diminution in lipase activity. 

Most partially saturated ring systems, 2,3-dihydro-l,4-dioxin 10 (sometimes named as 1,4-dioxene), 2,3-dihydro-1,4-dithiin 11, 2,3-dihydro-l,4-oxathiin 12, 2,3-dihydro-l,4-benzodioxin or 1,4-benzodioxane 13, 2,3-dihydro-l,4-benzodithiin 14, and 2,3-dihydro-l,4-benzoxathiin 15 are well investigated. Ring numbering for compounds 10-12 is followed as shown, independently of the presence of substituents. 

The potential energy barrier of 1,4-benzodioxan 13 to ring inversion is 1-2 kcal moP lower than that of 1,4-dioxene 10, typically 6.9 and 8.7 kcalmoP (HF/6-31G ) and 7.5 and 8.8kcalmoP (B3LYP/6-31G ), respectively <1998MI173>. 

Dithiin, 1,4-benzodioxin, and its 2-substituted derivatives can be readly deprotonated and trapped with electrophiles although the reaction is more problematic with 1,4-dioxin. Oxanthrene and phenoxathiin are cleaved with lithium <1996CHEC-II(6)447>. A more recent example deals with the metallation at C-3 of the 1,4-benzodioxane 60 bearing a carboxylic acid function at C-2, with lithium diisopropylamide (EDA) and subsequent quench with iodomethane. The corresponding 3-methylated benzodioxane 61 was isolated in 70% yield (Equation 6) <2000EJM663>. 

Numerous different mechanistic approaches have been applied for this combination. First, cyclization of phenoxy-ethanols 203, in the presence of (diacetoxyiodo)benzene and iodine, gave a mixture of 1,4-benzodioxane 13 and 6-iodo-l,4-benzodioxane 204 via alkoxy radicals (Equation 36) <1997J(P 1)787, 1996TL2441>. 

Finally, Buchwald and co-workers developed a high-yield, general method for the palladium-catalyzed formation of 1,4-benzodioxane. Bulky, electron-rich o-biphenylphosphines of type 214 together with Pd(OAc)2 have proved to be the most general catalytic system to avoid the /3-hydride elimination side reaction <2000JA12907>. This strategy was extended to the synthesis of enantiomerically pure 2-substituted-l,4-benzodioxanes 213 from 212 (Equation 37) <2001JA12202>. 

Whereas 2-substituted 1,4-benzodioxanes are attacked predominantly at the 7-position in Aiaj-DMA-promoted Friedel-Crafts reactions, the corresponding benzodioxin gives mainly the C-6 acylated product <99TL3523>. 

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