Hydroxymethylated products

The etherified hardwood lignin model II reacted at a similar rate as the phenolic model indicating the etherification of the phenolic group has a small effect on the reaction rate. When this reaction was repeated at 55°C with an excess formaldehyde, some mefa-hydroxymethylated products were obtained (Fig. 4B). 

The initially formed oxocarbenium ion intermediate may be intercepted by the acetonide oxygens to form oxonium ion species (depicted below). Acetonide rupture with eventual loss of acetone yields benzylidene acetals (e.g., A and B), which equilibrate via C to afford the axial hydroxymethyl product. Alternatively, in the presence of the water formed, the acetonide may hydrolyze to provide a more direct route to C. 

This new general synthetic method utilizes the well-known S2Os2 /Ag1 redox system. The first step is the formation of the alkoxyl radical by Ag(II) electron transfer oxidation. The fast (3-scission gives the nucleophilic CH2OH radical which adds to the protonated substrate. As already seen, the intermediate is oxidized by S2Os2 /Ag2 species, affording the hydroxymethylated products. 

The related Mannich reaction is not common. Under the usual acidic reaction conditions TV-substitution occurs, but this is a reversible reaction in the presence of base. Therefore, in basic medium, C- substituted products accumulate, and all positions can be substituted. 2-Methylimidazole gives 1,4,5-tri, 4,5-di- and 4-mono-substituted products. The observation that with formaldehyde and hydrochloric acid histamine gave (98) is at variance with the apparent requirement for basic medium. Since 1-substituted imidazoles do not react it is likely that the imidazole conjugate base is the reactive species. Unless imidazoles contain activating substituents they are not very susceptible to reaction with aldehydes (except HCHO) and ketones. An exception appears to be the product (99) of interaction between imidazole and hexane-2,4-dione. An activated compound such as 4-methylimidazoline-2-thione gives the 5-dimethylamino compound (100) imidazoline-2-thione gave only the (V-hydroxymethyl product under the same reaction conditions. Imidazolin-4-ones with a free 5-position readily form benzylidene derivatives (B-76MI40701). 

Unlike the radical approaches mentioned above, Vasella exploited a carbanion approach. Thus, the anomeric carbanion was anticipated to be stabilized by the Cl-carboxylate group. A 1-deoxy derivative of Neu5Ac 198 was treated with LDA, and the resulting anion was reacted with formaldehyde to produce a 3/1 mixture of a- and /3-isomers of 2-hydroxymethyl product 199 (O Scheme 55) [131]. 

A very convenient hydroxymethylation process has been developed based on the Sml2-mediated Bar-bier-type reaction. Treatment of aldehydes or ketones with benzyl chloromethyl ether in the presence of Smh provides the alkoxymethylated products in good to excellent yields. Subsequent reductive cleavage of the benzyl ether provides hydroxymethylated products. Even ketones with a high propensity for enolization can be alkylated by this process in reasonable yields. The method was utilized by White and Soners as a key step in the synthesis of ( )-deoxystemodinone (equation 27). This particular ketone substrate resisted attack by many other nucleophilic reagents (such as methyllithium) owing to conpeti-tive enolate formation. 

Hydroxylation of terminal methyl groups of the alkenyl side-chain to give c/s and trans (major) alcohols Oxidation of hydroxymethyl product of the alkenyl side-chain to carboxylic acids Reduction of alkenyl side-chain and oxidation of terminal methyl group... 

Dimethylimidazole, however, gives the 5-hydroxymethyl derivative, and though it is usually difficult to induce substrates with electron-withdrawing groups to react, l-methyl-5-nitroimidazole forms the 2-hydroxymethyl product (see CHEC-I). Whilst the reaction mechanism is uncertain, it could involve A(-hydroxymethylation followed by rearrangement. Examples include 2-hydroxy-methylation of l,4-dimethyl-5-nitroimidazole in DMSO <87JMC150>, and 5-substitution of 4-bromo-... 

The base-catalyzed aldol addition reaction of cyclic ketones with formaldehyde is limited by the propensity of the initial hydroxymethyl products to undergo subsequent reactions (e.g. equations 62 and 63). - - Similar problems occur with enolizable aliphatic aldehydes. 

Metabolic stability in cephalosporins is achieved primarily by varying the chemistry on the C-3 position from the hydrolyzable acetoxymethyl function seen in several of the first-generation drugs. Hydrolysis to the hydroxymethyl product invariably results in an inactive or much weaker antibacterial. Table 6-6 illustrates the variations utilized. Ceftizoxime solves the problem by simply having no substituent at C-3. As a result no metabolism occurs. 

Reference has been made to an 8-hydroxymethyl product arising from oxidation studies and from this an 8-formyl compound might well be expected to arise. The 5-formyl compound has been synthesised by the oxidation of a-tocopherol with dioxane dibromide by way of a bromoquinone intermediate (ref. 134). 

Oxidation of ADP using periodate, followed by partial reduction with boro-hydride, affords a mixture of the fully reduced bis(hydroxymethyl) product and the semialdehydic reduction intermediate. By dint of comparison with model compounds using n.m.r. spectrometry, it has been shown that the first reduction step takes place at C-3, to give (107) (which will prefer to cyclize to the hemiacetal). It is not clear why preferential reduction at C-3 occurs either the aldehydic group at this position is more reactive per se, or it is more accessible to borohydride. It seems likely that (107) and its analogues could prove to be useful new affinity labels. 

However, conditions have been established for the production and isolation of bis(pyrrol-2-yl)methane itself from treatment of pyrrole with aqueous formalin in acetic acid from reaction with formalin in the presence of potassium carbonate a bis-hydroxymethylation product is obtained. This reacts with pyrrole in dilute acid to give tripyrrane and from this, as the scheme shows, reaction with 2,5-bis(hydroxymethyl)pyrrole gives porphyrinogen which can be oxidised to porphyrin. 

Redaction of 17o-ethinyl-17 -hydroxy-2-hydroxymethylene-4-androsten-3-one by Rhizopus stolontfer to the corresponding 2a-hydroxymethyl product. 

The hydroxymethylated products formed are isolable from the reaction mixture and this has allowed the kinelie coefficients, k, shown in equation 13 to be determined. An example for quantification of the rate constants is given in seetion 11.B.2. 

Whereas the cyclic carbonate (23) reacts with tributylstannane to give only the expected 3-deoxy-3-C-hydroxymethyl product (24), the corresponding -hydroxyethyl derivative (25) gave both the deoxy product (26) and the 3-C-ethyl branched-chain isomer (27), the ratio depending on the concentration of the reactants. 

L-Prohne catalyzes the direct hydroxymethylation of aldehydes and ketones, though with low yields [116]. Higher yields and enantioselectivities are generated by a,a-diphenylprolinol trimethylsilyl ether [117]. The desired a-substituted P-hydroxymethylated products are not stable and have to be converted to more readily isolable derivatives. This method should be the first choice for synthesis of a-hydroxymethylated aldehydes since it is suitable for large scales (75.8 g of aldol). 

It appears that the in vitro reaction must be in the form of the N -hydroxymethyl product, and this may well be the active mutagen. However, subsequent in vivo cross-linking could still form dimeric products, particularly when two appropriate molecules, one N -hydroxymethylated and the other not, come into a stereochemically appropriate relationship for methylene-bridge formation. 

The a- and B -glycosides (39) have been individually prepared as substrates for a glycosiduronase.Hydrogenation of the enal (40) gave mainly the L-arabino-aldehyde which could be epimerized in al]fali to the D-xylo-analoque. Reduction of (40) with surprisingly poor yielding and the hydroxymethyl product afforded... 

Tolbutamide, hypoglycemic Rat and rabbit oxidation to hydroxymethyl product (M) carboxy derivative (m) UP in urine. Contrasted to early... 

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