Hydroxymethylation, and

Michael-type addition, hydroxymethylation and Mannich reaction take place at nitrogen to give the corresponding 2-substituted 4-hydroxyphthalazin-l(2/f)-ones. 

In many cases, substituents linked to a pyrrole, furan or thiophene ring show similar reactivity to those linked to a benzenoid nucleus. This generalization is not true for amino or hydroxyl groups. Hydroxy compounds exist largely, or entirely, in an alternative nonaromatic tautomeric form. Derivatives of this type show little resemblance in their reactions to anilines or phenols. Thienyl- and especially pyrryl- and furyl-methyl halides show enhanced reactivity compared with benzyl halides because the halogen is made more labile by electron release of the type shown below. Hydroxymethyl and aminomethyl groups on heteroaromatic nuclei are activated to nucleophilic attack by a similar effect. 

Halogenomethyl, hydroxymethyl and aminomethyl groups readily undergo displacement reactions with nucleophilic reagents. Both side-chain and nuclear substitution products have been obtained (Scheme 57). These two possibilities are exemplified by the reaction of furfuryl chloride with sodium cyanide (Scheme 58). 

Simple alkyl radicals such as methyl are considered to be nonnucleophilic. Methyl radicals are somewhat more reactive toward alkenes bearing electron-withdrawing substituents than towards those with electron-releasing substituents. However, much of this effect can be attributed to the stabilizing effect that these substiments have on the product radical. There is a strong correlation of reaction rate with the overall exothermicity of the reaction. Hydroxymethyl and 2-hydroxy-2-propyl radicals show nucleophilic character. The hydroxymethyl radical shows a slightly enhanced reactivity toward acrylonitrile and acrolein, but a sharply decreased reactivity toward ethyl vinyl ether. Table 12.9 gives some of the reactivity data. 

Scheme 11. Proposed quinone methide condensation mechanism. Work by Murray (and Lemon unpublished) showed clearly that the quinone methides formed from o-hydroxymethyl and not /7-hydroxymethyl groups in the presenee of ester.

Hydroxymethylation and alkylation of furans, thiophenes, and pyrroles in the presence of H" " cations 98KGS3. 

Isoxazoles are known at present to undergo the following electrophilic substitution reactions nitration, sulfonation, halogenation, chloroalkylation, hydroxymethylation, and mercuration. Repeated attempts to effect the Friedel-Crafts reaction in the isoxazole series in the authors laboratory failed. The isoxazole nucleus seems not active enough to react with weak electrophilic reagents. 

Fig. 30. — Packing arrangement of 4-fold antiparallel double helices of potassium hyaluronate (32). (a) Stereo view of a unit cell approximately normal to the line of separation of the two helices. The two chains in each duplex, drawn in open and filled bonds for distinction, are linked by not only direct hydrogen bonds, but also water bridges. Inter double-helix hydrogen bonds are mediated between hydroxymethyl and iV-acetyl groups. Potassium ions (crossed circles) at special positions have only a passive role in the association of hyaluronate chains.

Similar experiments with 1-methyl- and 2-methylnaphthalene involved oxidation of the methyl group to hydroxymethyl and carboxyl groups (Cemiglia et al. 1984a,b). 

A major route of metabolism for (67) and (73) is oxidation at the C9 position to form hydroxymethyl and carboxyl metabolites. The hydroxymethyl metabolites are potent CBi agonists with pharmacological profiles similar to the parent compounds, while the carboxy metabolites have reduced activity [115] the 9-carboxy analogue of (73) does not bind to the CBi receptor [93]. 

Of the direct methyl group replacements reported, small groups such as hydroxymethyl and fluoromethyl are tolerated, while larger groups in this position result in compounds with reduced in vivo potency and efficacy. The n-butyl derivative (159) was the only C9 methyl replacement analogue that showed a marked effect on hypothermia (5°C decrease at 168/rmol/kg ED50 not calculated) [116]. 

The CBi binding affinity of the hydroxymethyl and carboxyl analogues can be increased by substituting the C3 pentyl side chain for a dimethylheptyl side chain (Table 6.13). 1 l-Hydroxy-l, l -DMH A -THC, HU-210 (165), is an extremely potent cannabinoid agonist that has been widely used as a pharmacological tool [119]. Its ( + ) enantiomer, HU-211 (dexanabinol), which is in clinical development for the treatment of cognitive disorders, does not have high affinity for CBi receptors [120]. 

The 8-methyl-8,14-cycloberbine 364, derived from the protoberberine 324 via the betaine 363, was reduced with sodium borohydride or lithium aluminum tri-tert-butoxyhydride to give a diastereoisomeric mixture of cis-and trans-alcohols (7.8 1 or 1 7.8, respectively) (Scheme 64).t)n exposure to formaldehyde the mixture underwent N-hydroxymethylation and subsequent intramolecular substitution on the aziridine ring to give the oxazolidine 365. Removal of the hydroxyl group in 365 was accomplished by chlorination followed by hydrogenolysis with tributyltin hydride. Reductive opening of the oxazolidine 366 with sodium cyanoborohydride afforded ( )-raddeanamine (360), which has already been converted to ochotensimine (282) by dehydration. 

Analysis of the Murchison meteorite led to a completely different type of phosphorus compound the only phosphorus-containing compounds found were alkanephos-phonic acids. Spurred on by these results, de Graaf et al. (1995) irradiated mixtures of o-phosphorous acid in the presence of formaldehyde, primary alcohols or acetone with UV light (low pressure Hg lamp, 254 nm with a 185-nm component) and obtained phosphonic acids, including hydroxymethyl and hydroxyethyl phosphonic acids, which had been found in the Murchison meteorite. Alkanephosphonic acids can be derived from phosphorous acid, with a P-H bond being replaced by a P-C bond. 

To summarize briefly, our approach involves initial attack by a relatively nucleophilic metal hydride on coordinated CO. Such reactivity has been demonstrated repeatedly for main-group metal hydrides perhaps the most elegantly worked-out system involves CpRe(C0)2(N0)+ (Cp = Tl-C H ) which, under varying conditions, can be converted to an entire range of products containing CO at different stages of reduction, including formyl, carbene, hydroxymethyl and methyl species (Scheme l). Reactions lead-... 

An excellent example of this sequence was illustrated in the reaction of CpRe(C0)2(N0)+ with NaBHu which under carefully controlled conditions produced the formyl, the hydroxymethyl and the methyl complexes, successively.— —... 

Table 6.21 Overall performance of selected methods in predicting barriers for the addition of methyl, hydroxymethyl and cyanomethyl radicals to substituted alkenes. ...

K. B. Sloan, N. Bodor, Hydroxymethyl and Acyloxymethyl Prodrugs of Theophylline Enhanced Delivery of Polar Drugs through Skin , Int. J. Pharm. 1982, 12, 299-313. 

Steller, W.A. and Brand, W.W. Analysis of dimethoate-treated grapes for the V-hydroxymethyl and de-Wmethyl metabolites and for their sugar adducts, J. Agric. Food Chem., 22(3) 445-449, 1974. 

Folic acid is a complex molecule centrally involved in the metabolism of one-carbon molecular fragments the methyl, hydroxymethyl, and formyl groups. 

The hydroxymethyl and carboxyl group of Ser can participate in pyrazole-ring formation, as shown in the transformation of A -protected L-Ser with the Mitsunobu reagent into a /3-lactone which afforded the N-protected serine hydrazide upon treatment with methyl hydrazine. Cyclization to 25 was achieved by diisopropyl azodicarboxylate (DIAD) and TPP [90H(31)79]. 

Flavanones with C-Methyl, C-Hydroxymethyl, and C-Formyl Substituents Reported from 1992 to 2003... 

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