Hydroxymethyl substituent

Condensation reactions between two hydroxymethyl substituents eliminate water to form ether linkages (Fig. 7.23a) or eliminate both water and formaldehyde to form methylene linkages (Fig. 7.23b). Ether formation is favored under neutral or acidic conditions and up to 130°C above which formaldehyde departs and methylene linkages are generated. The methylene linkage formation reaction, which eliminates water and fortualdehyde, is more prevalent under basic conditions. Condensation reactions between hydroxymethyl groups and reactive... 

As the reactions proceed, the disappearance of phenol is delayed due to competition for reaction with formaldehyde between phenol and the faster reacting hydroxymethyl-substituted phenols. Competition also exists between formaldehyde substitution reactions and condensation reactions between rings. Condensation reactions between two ortho-hydroxymethyl substituents are the least favorable condensation pathway. Depending on the reaction conditions, substitutions occur... 

Condensation reactions of hydroxymethyl groups on phenolic resoles and amines on melamine take place between pH 5 and 6 (Fig. 7.33). Only selfcondensations of hydroxymethyl substituents occur under strongly acidic or basic conditions. 

Hydroxymethyl-4,6-dimethylphenol, 406 Hydroxymethylphenol. See also Hydroxymethylated phenol reaction with melamine, 411 reaction with urea, 410 Hydroxymethyl substituents, condensation reactions of, 403... 

Ortho-hydroxymethyl substituents, 401 Ortho-ortho methylene linkages, 393,... 

When Shallenberger and coworkers attempted to explain the sweetness of /8-D-fructopyranose, they intuitively assigned the anomeric 2-hydroxyl group as AH and the oxygen atom of the 2-(hydroxymethyl) substituent as B. This assignment has since been supported by Lindley and Birch. It was shown that 1,5-anhydro-D-mannitol (15, 2-deoxy-D-fructopyranose ) and jS-D-arabinopyranose (22) (in both of which, one of the AH or B units... 

Quinolones possessing a 7-(3-aminopyrrolidin-l-yl) substituent are particularly potent antibacterial agents. However, they often have very low solubility. Based on the observations that the hydroxymethylpyrrolidine (38) is significantly more potent against bacteria than its enantiomer (39) (the hydroxymethyl substituent in (39) apparently has a deleterious effect on activity while the same substituent in (38) has little effect on potency based on comparisons with the unsubstituted pyrrolidine analogue (40)) [84] and the enantiomer (41) is at least as potent as,... 

Another entry into useM five-carbon building blocks from d-xylose encompasses the expeditious four-step protocol for the l-phenylpyrazol-3-carboxaldehyde with a 5-hydroxymethyl substituent (Scheme 2.15) and the various follow-up reactions feasible. 

TriOH-8,5 -diOMe-6,7-methylenedioxy-flavanone (plumbaginol, 343) Dihydroflavonol aglycones with C-methyl and C-hydroxymethyl substituents... 

The major pathways for the fragmentation of kojic acid (81,5-hydroxy-2-hydroxymethyl-pyran-4-one), are shown in Scheme 14 support for each route was provided by the appearance of metastable ion peaks (67MI22203). An RDA cleavage followed by loss of a CH2OH radical produces ion (81a), m/e 69, the structure of which was substantiated by deuteration experiments. The ion at m/e 97 arises by extrusion of CO from the molecular ion and loss of HO- from the side chain structures (81b) and (81c) were proposed. Decomposition of [M]t occurs to give ethylene and an HC=0 fragment. The initial stage involves loss of a -CHO radical from the hydroxymethyl substituent, a process which has... 

On the basis of the success of these initial reports on the proline-catalyzed intramolecular aldol reaction several groups focused on extending this type of synthesis to bicyclic products bearing angular substituents other than methyl and ethyl reported earlier [97-101]. Preparation of bicyclic systems with protected hydroxymethyl substituents, e.g. 99, was reported by Uda et al. (Scheme 6.46, Eq. 1) [113, 114]. As a selected example, the aldol adduct 99 was formed in 70% yield and with 75% ee in the presence of one equivalent of L-proline. Synthesis of a related product with an angular phenylthio substituent, 101, was described by Watt and co-workers (Scheme 6.46, Eq. 2) [115]. After intramolecular proline-catalyzed aldol reaction, dehydration of the ketol intermediate, and subsequent recrystallization... 

In CHEC-II(1996), carbene insertion reactions into the N-H bond to form a fused-ring azetidinone warranted a separate section. In the last decade, the popularity to this approach to bicyclic systems seems to have markedly declined. Nevertheless, dirhodium tetraacetate and rhodium octanoate were used to generate the corresponding bicyclic compounds from the diazo compounds 241 (R2 = H and /3-Me), respectively, via the carbene intermediates. In the latter case, the produced enol was esterified and then the ester group replaced with a hydroxymethyl substituent to give derivatives 242 in a one-pot process <2001JCM166, 1999TL427>. 

Sometimes the phosphorane is isolated and the cyclization step is achieved by heating the compound in an inert solvent such as toluene. In this way carbapenems with useful 2-hydroxymethyl substituents (see Section 2.04.7.2) can be prepared. For example, the phosphorane 297 has been cyclized to compound 298 <1998H(48)2287>. 

The use of biosynthetic methods to stereoselectively acylate iV-hydroxymethyl substituents on some bicyclic /3-lactams has been mentioned in Section 2.04.8.1 <2003TA3805>. 

Using established methods, pyrrolizidines with 1- and 2-hydroxy and 1- and 2-hydroxymethyl substituents have been synthesized.3 The racemates were separated by chromatographic techniques, and resolved by classical methods. 

Ishikawa T, Shimizu Y, Kudoh T, Saito S (2003) Conversion of D-glucose to cychtol with hydroxymethyl substituent via intramolecular silyl nitronate cycloaddition reaction application to total synthesis of (+)-cyclophelhtol. Org Lett 5 3879-3882... 

For gentamycin derivatives, the introduction of an axial hydroxymethyl substituent at C-1 in the 2-deoxystreptamine moiety reportedly ameliorates nephrotoxicity and confers protection against inactivation by bacterial enzymes. The Belgium team investigated a similar modification in the kanamycin B series [265]. As expected, l-C-(hydroxymethyl)kanamycin B (212) proved equipotent with the parent aminoglycoside (208) against kanamycin B-sensitive bacteria and the introduction of a 6"-azido, 6"-chloro, or 6"-acetamido group (213)-(215), did not reduce antibacterial activity Table 3.19). However, the introduction of a l-C-(hydroxymethyl)... 

Further activation and functionality is introduced to cyclopropyl ketones or esters by an additional hydroxymethyl substituent or its equivalent. On this basis, a synthesis of a-methylene y-butyrolactones has been performed (equation 52). ... 

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