Benzodioxane synthesis

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. 

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]. 

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

Cyclizations of o-(a -haloalk oxy)phenols have been widely studied and were used to afford an expedient synthesis of 5-alkyl-2,3-dihydro-l,4-benzodioxins <2004SC2487>. This approach via a nucleophilic substitution was used for the synthesis of 8-substituted-2-hydroxymethyl-l,4-benzodioxane derivatives 164 in an enantiopure form. Use of CsF instead of more basic conditions allowed higher yields and enantiomeric excess (Equation 28) <2001ASC95>. Dry tetrabutylammonium fluoride (TBAF) in THF was required and was basic enough to initiate an intramolecular Sn substitution from the protected phenol 165 to the fluoro-l,4-benzodioxane 166 <1996T6187>. 

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>. 

In a similar approach, Kasture and coworkers describe the use of neat substrate (ethyl acetate both as alcohol donor and as the reaction medium) in the preparation of chirally pure S-(-)-l,4-benzodioxan-2-carboxylate, an important drug intermediate used in the synthesis of doxazosin mesylate, from racemic l,4-benzodioxan-2-carboxylic acid [138]. Again, CaLB catalyzed the transesterification reaction with good enanhoselectivity (E = 160) and acceptable enantiomeric excess (>95%) and chemical yield (50%). 

Benzodioxanes (6, 516). The earlier synthesis of benzodioxanes by oxidative coupling of catechol derivatives with methoxypropenylphenols has been extended to the first synthesis of the complex benzodioxane silybin (3) shown in equation (I).2 The starting materials are (2R,3R)-dihydroqucrcctin (I) and coniferyl alcohol (2). In this case, the reaction is not regioselective, 3 and the isomeric 4 being obtained in nearly equal amounts. 

Routes to benzo-fused derivatives of 1,4-dioxanes, 1,4-oxathianes and 1,4-dithianes make use of anions or dianions of the appropriate 1,2-disubstituted benzene. An alternative approach to the synthesis of 1,4-benzodioxanes involves Diels-Alder addition reactions of alkenes across the quinone function of 1,2-benzoquinones, e.g. (352) — (353). 

Nitrilase from Rhodococcus R312 was found to be (/ )-enantiospecific toward 2-cyano 1,4-benzodioxane, in contrast to other screened nitrilases that showed (5)-preferences however, the anthors do not report on the absolute configuration of the enantiopure synthesized l,4-benzodioxane-6-formyl-2-carboxylic acid. An organic cosolvent was added to the reaction mixtnre to increase solubihty of substrates (Table 17.7). A possible hypothesized application of enantiopure l,4-benzodioxane-2-carboxylic acid is the synthesis of doxazosine methylate, member of the quinazoline family of drugs, and indicated for the treatment of hypertension. 

Amoldi A, Amone A, Merlini L (1984) Synthesis of the Natural Coumarinolignoids Propa-cin and Cleomiscosin A and B. An Empirical Spectroscopic Method to Distinguish Regioi-somers of Natural Benzodioxane Lignoids. Heterocycles 22 1537... 

An asymmetric synthesis of 2,3-disubstituted 1,4-benzodioxanes is based on the cyclisation of the protected diol 38, a Mitsunobu-derived substrate, which probably involves a quinone methide <03TA701>. An efficient resolution of 1,4-benzodioxane-2-carboxylic acid has been described <03TA3779>. 

Highly reactive quinone methide can be utilized as intermediates in organic synthesis. From the viewpoint of biomimetic synthesis, silybin (782) bearing a benzodioxane skeleton was synthesized in 44.5% yield, together with isosilybin (784) (33.5%), by AgiO-mediated oxidation of equimolar amounts of 27 ,37 -dihydroquercetin (783) and coniferyl alcohol (298) in benzene-acetone. The p-quinone methide 785 must be generated as a reactive intermediate (Scheme 156) °. 

Buchwald et al. demonstrated that the intramolecular palladium-catalyzed C—O bond formation was an attractive means to assemble the oxygen heterocycles 557 (Scheme 170).243 They applied this methodology to the synthesis of MKC-242 (560), a benzodioxane antidepressant (Scheme 171).243b... 

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