Acid-Catalyzed Hydroxymethylations

PRINS KRIEWITZ Hydrexymslliyiation Acid catalyzed hydroxymethylation of akeras. 1,3-Dk>xafia synthesis. 

Although acid-catalyzed hydroxymethylation is not a practical possibility, by the addition of a reducing agent to the reaction mixture overall reductive alkylation can be achieved (Scheme 21). 

PRINS-KRIEWITZ Hydroxymethylation Acid catalyzed hydroxymethylation of alkenes (see 1st edition). 

Continuing the retrosynthetic analysis, we perform FGl, interconversion of the protecting acetonide unit to the hydroxymethyl and phenol group. The hydroxymethyl group is introduced by acid-catalyzed hydroxymethylation of phenol and is therefore disconnected in the last step, affording the easily available para-hydro-xybenzaldehyde and formaldehyde. 

Hexachlorophene (margiii) is a skin germicide formerly used in soaps. It is prepared in one step from 2,4,5-trichlotDphenol and formaldehyde in the presence of sulfuric acid. How does this reaction proceed (Hmt Formulate an acid-catalyzed hydroxymethylation for the first step.)... 

Bromomethyl)- or (hydroxymethyl)cycIopropane derivatives undergo acid-catalyzed homoallyiic rearrangements to yield trans-olefins (J.P. McCormick, 1975 S.F. Brady, 1968 M. Julia, 1974). This rearrangement is the basis of Julia s terpene synthesis (see. p. 70). 

The study on 2,7-di-rerf-butylthiepin has recently been extended to explore more simply substituted thiepins 58). The palladium-catalyzed reaction of the diazo compound 107 lacking a 4-methyl substituent gives exclusively the exo-methylene compound 108 whereas the acid-catalyzed reaction of the same precursor 107 resulted in the formation of 2,7-di-/er/-butyl-4-ethoxycarbonylthiepin (109)58). Due to the substantial thermal stability of 109 it is possible to transform the ethoxy-carbonyl group into the hydroxymethyl (110), trimethylsilyloxymethyl (111) and formyl group (112)58). 

S. Kobayashi, Lanthanide Trifluoromethanesulfonates as Stable Lewis Acids in Aqueous Media. Yb(OTf)3 Catalyzed Hydroxymethylation Reaction of Silyl Enol Ethers with Commercial Formaldehyde Solution Chem Lett. 1991, 2187-2190. 

The base lability of succinoyl diester hnker severely limits the selection of protecting groups available for an oligosaccharide synthesis, so a more versatile tether was required. Diether bonds of benzylphenol or dibenzyl of 1,4-di(hydroxymethyl)-benzene satisfy this requirement because they are stable to both bases and to acids. A sufficient acid stability is important since the formation of a glycosidic bond is an acid-catalyzed reaction, not surprisingly, as it is an acetal functionality. For instance, DOX,34 the dibenzyl hnker a,a -DiOxyXylyl diether, -0CH2C6H4CH20-, is not limited by restriction of the succinoyl hnker (1) when bound via a hydroxyl or as an... 

D-glucose and D-fructose in acidified deuterium oxide, and acid conversion of D-[2- H]glucose were conducted, in order to determine the importance of 39 as an intermediate from the proportion of deuterium incorporated at C-3 of 5-(hydroxymethyl)-2-furaldehyde. However, the 2-furaldehyde formed in the reactions contained no deuterium. Thus, an essentially irreversible sequence that involves hexose, 36, 38, 40, and 11 best explains the acid-catalyzed, dehydration reaction. 

Thermolysis of D-fructose in acid solution provides 11 and 2-(2-hydrox-yacetyl)furan (44) as major products. Earlier work had established the presence of 44 in the product mixtures obtained after acid-catalyzed dehydrations of D-glucose and sucrose. Eleven other products were identified in the D-fructose reaction-mixture, including formic acid, acetic acid, 2-furaldehyde, levulinic acid, 2-acetyl-3-hydroxyfuran (isomaltol), and 4-hydroxy-2-(hydroxymethyl)-5-methyl-3(2//)-furanone (59). Acetic acid and formic acid can be formed by an acid-catalyzed decomposition of 2-acetyl-3-hydroxyfuran, whereas levulinic acid is a degradation prod-uct of 11. 2,3-Dihydro-3,5-dihydroxy-6-methyl-4//-pyran-4-one has also been isolated after acid treatment of D-fructose.The pyranone is a dehydration product of the pyranose form of l-deoxy-D-eo f o-2,3-hexodiulose. In aqueous acid seems to be the major reaction product of the pyranone. 

In connection with the enantioselective alkylation of Pro or 4-hydroxy-proline, the azabicyclo[3.3.0]octane system 81 was obtained after reaction with pivaldehyde (81HCA2704 85HCA155). In a more complex transformation A-protected L-Pro was transformed into the same bicyclic system (Scheme 49) (81JA1851 84JA4192). The product was prepared as a model substance in the total synthesis of pumiliotoxin. A related compound 82 was prepared from 5-(hydroxymethyl)-2-pyrrolidinone (prepared from L-pyroglutamic acid) by an acid-catalyzed condensation with benzaldehyde (86JOC3140). 

Epoxidation of 632c with m-CPBA to 634, followed by silylation with bis(trimethylsilyl) acetamide (BSA) to 635, and TMSOTf-indnced cyclization gives 6-hydroxymethyl-3-phenyl-l,2,4-trioxane 636 (Scheme 181) °. Epoxides 638, which are characterized by geminal dimethyl substitnents, are obtained by m-CPBA oxidation of the (0-3,3-dimethyl-allyl)hydroperoxy acetals 637. While the strnctnral change in 638, as compared to epoxide 634, direct the acid-catalyzed cyclizations to the endo mode yielding the 7-membered... 

Scheme 6 Fructose can be transformed into 5-hydroxymethyl furfural (HMF) via acid-catalyzed dehydration. Solid acid catalysts applied to facilitate the reaction are zeolites, ion-exchange resins and solid inorganic phosphates. With sporadic success, notably with inorganic phosphates, other carbohydrate sources such as inulin can also be transformed into HMF.

When a 4-methyl group is present, the reaction follows a different course (Section IV,D,l,c) earlier claims of an acid-catalyzed rearrangement to the isomeric 4-hydroxymethyl-l//-imidazole were later corrected. ... 

The formation of furan derivatives in acid-catalyzed dehydrations of carbohydrate substrates is a well known reaction, first reported by Dobereiner186 in 1832. Among the plethora of compounds formed, 2-furaldehyde is the main product obtained from all of the pentoses, whereas 5-(hydroxymethyl)-2-furaldehyde is the major product... 

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