N- or C-hydroxymethylation

Pyrrole has been condensed under alkaline conditions with formaldehyde to give products of either N- or C-hydroxymethylation (Scheme 22). Although acid-catalyzed hydroxy-methylation is not a practical possibility, by addition of a reducing agent to the reaction mixture overall reductive alkylation can be achieved (Scheme 23). 

Pyrrole has been condensed under alkaline conditions with formaldehyde to give products of either N- or C-hydroxymethylation (Scheme 20). 

Imidazoles substituted in the 1-position can be hydroxymethylated at C-2 with formaldehyde or paraformaldehyde,400,401 whereas imidazoles unsubstituted at N-l are hydroxymethylated at C-4 or C-5. For example, 4-methylimidazole yields 4-methyl-5-hydroxy-methylimidazole.402 If there is a deactivating substituent in the ring (e.g., 4-nitroimidazole) hydroxymethylation will not take place. Thermal condensation of N-substituted imidazoles with other aldehydes (except acetaldehyde) or the reaction of aldehydes with 2-lithioimidazoles results in the formation of 2-hydroxyalkylimida-zoles.210... 

Figure 22-6 The Q and Q syntheses using Co2(CO)8 as precursor (adapted from H, M. Feder and J. M. Rathke, Ann. N.Y. Acad. Sci., 1980, 333, 45). Note that H transfer to coordinated formaldehyde A, can give a methoxide B, or a hydroxymethyl C, either of which can then be reduced by H2 or can insert CO, the product of which is then reduced. The HCo(CO)3 is recycled.

It is of interest that, in 1882, lime-water treatment of lactose was found to yield the insoluble calcium a -D-isosaccharinate, a rearrangement product of the n-glucose component, and, in 1896 and 1899, Lobry de Bruyn and Alberda van Ekenstein" observed that treatment of lactose with either lead hydroxide or potassium hydroxide liberated n-galactose. Kiliani established the structure of the saccharinate as that of a 3-deoxy-2-C-(hydroxymethyl)pentonic acid and, had the mechanism of its formation been understood (see p. 188), this would have been sufficient evidence... 

Anilinotrimethylolmethane N-(Trimethylol-methane)-aniline P henylaminotrimethylol-methane N-Phenyl-(tris-hydroxymethyl)-methylamine 2-Anilino-2-hydroxymethyl-1,3-dihydroxypropane 2-Anilino-2-hydroxy-. methyl-1,3-propanediol or Phenyltrimethylol-methylamine, QHs. NH.C(CHjOH)j. This may be considered as the parent compd of the derivs described below ... 

The 1C conformation (51) of most of the D-hexoses is highly unfavored, because of the large, axial, hydroxymethyl substituent at C-5. Stabilization of the structure of D-idose is effected by the formation of the 1,6-anhydro derivative (52), which is formed in about 80% yield by thermodynamic equilibration in aqueous acid solution, the highest yield of 1,6-anhydride for any of the hexoses. It is obvious that, in 6-deoxy-(n or L)-idose, no such anhydride formation can occur and, since the 5-(7-methyl group requires somewhat less space than the 5-(hydroxymethyl) group of the hexose, a considerable proportion of the 1C conformation of 6-deoxy-D-idose may be present in this sugar. 

Figure 5 lists the aldehydes which were made in quantities ranging from 10 g to 10 kg. Figure 6 shown a representative NMR spectrum of the aldehyde taken from the unpurified residue after lypophilization of the reaction mixture. This spectrum illustrates the specificity of the enzyme. Initially, we were concerned about the possible formation of uronic acids reported by some authors (25-27). However, we have no evidence for the presence of these by-products from the carbon-13 spectra of the oxidation products. On the other hand, the small signals between 90 ppm and 103 ppm may belong to dimeric products described by Maradufu and Perlin (28), All the aldehydes are hydrated as indicated by the presence of a peak at 88.7 ppm and the absence of peaks below 200 ppm. These aldehydes are relatively stable in the presence of base as evidenced by preparation of 5-C-hydroxymethyl-L-arabino-hexopyranoses (Equation 1). Even though the synthesis was carried out in 1 N NaOH, very little by-products resulted from elimination or retroaldol reactions at the pyranose ring. 

Both H and n.m.r. measurements have indicated that a solution of o-hamamelose (2-C-hydroxymethyl-D-ribose) in either deuterium oxide or DMSO contains two furanose and two pyranose ( C ) forms. ... 

The H- and C-n.m.r. spectra of sucrose, methyl a-D-fructofuranoside (20) and methyl P D-fhictofuranoside (21) with single sites of C-substitution at C-1, C-2, C-3-, or C-6 of the furanose moieties have been analysed to assess the conformations of the their furanose rings, and of the glycosidic linkages in aqueous solution. In addition, spin-couplings in 20 and 21 were compared with those of a-(22) and p-D-r/jrco-pentulofuranose (23), respectively, to study the effect of glycosidation and hydroxymethyl substitution on the solution conformations. The conformations of 2-mono- and 2,2 -di-G-substituted a,a-trehalose derivatives 25 have been shown by n.m.r. spectroscopy in combination with molecular mechanics calculations, to differ from that of the 2,2 -unsubstituted disaccharide 24, both in solution and in the solid state. N.O.e. experiments on the 6 -deoxy-, 6 -thio-, and 6 -0-THP derivatives of methyl 2-acetamido-2-deoxy-P-lactoside, potential inhibitors of (2- 6)-a-sialyltransferase, proved that they adopt the same conformation as the parent compound. ... 

Fig. 8.20. Two-step activation ofN-[(acyloxy)methyl] prodrugs, a) Cleavage of the ester bond, which may be enzymatic and/or nonenzymatic, is followed by decomposition of the N-(hy-droxymethyl) intermediate, b) For (V-(hydroxymethyl) derivatives of amides and imides, the decomposition is base-catalyzed, c) For N-(hydroxymethyl) derivatives of amines, the decomposition can be uncatalyzed or undergo acid or base catalysis (modified from [214]).

Furthermore, (L)-proline and paraformaldehyde give (L)-N-hydroxymethyl-proline (as the iminium carboxylate -i- H2O) upon large scale milling and stoichiometric millings of imidazole (0 °C) or benzimidazole (r. t.) with (HCHO) quantitatively provide the corresponding solid 1-imidazolylmethanols [22]. 

All presently known phosphamethin-cyanines were prepared according to our original procedure (1964) in which two quaternary salts of a heterocyclic base (e. g. 4) are condensed with tris-hydroxymethyl-phosphine 5 in the presence of a proton-abstracting base The preparation ofbis-[N-ethyl-benzothiazole(2)]-phosphamethin-cyanine-tetrafluoroborate 6 illustrates the synthetic sequence. A mixture of 2 moles of N-ethyl-2-chlorobenzothiazolium-tetrafluoroborate 4 and 1 mole of tris-hydroxymethyl-phosphine 5 in dimethylformamide is slowly reacted with ethyl-di-isopropylamine or pyridine at 0 °C. Addition of water immediately affords the crystalline cyanine dye 6 in ca. 45% yield ... 

Polystyrene-bound amines can be converted into the corresponding phthalimides by heating with other phthalimides (BuOH, 85 °C, 18 h [33]). Support-bound phthalimides have also been prepared by N-alkylation of phthalimide derivatives [295] or by amidomethylation of cross-linked polystyrene with /V-(hydroxymethyl) or /V-(chloro-methyl)phthalimide [296,299]. 

Standard solid-phase peptide synthesis requires the first (C-terminal) amino acid to be esterified with a polymeric alcohol. Partial racemization can occur during the esterification of N-protected amino acids with Wang resin or hydroxymethyl polystyrene [200,201]. /V-Fmoc amino acids are particularly problematic because the bases required to catalyze the acylation of alcohols can also lead to deprotection. A comparative study of various esterification methods for the attachment of Fmoc amino acids to Wang resin [202] showed that the highest loadings with minimal racemization can be achieved under Mitsunobu conditions or by activation with 2,6-dichloroben-zoyl chloride (Experimental Procedure 13.5). iV-Fmoc amino acid fluorides in the presence of DMAP also proved suitable for the racemization-free esterification of Wang resin (Entry 1, Table 13.13). The most extensive racemization was observed when DMF or THF was used as solvent, whereas little or no racemization occurred in toluene or DCM [203]. 

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