Imidazoles hydroxymethylation

Imidazoles are hydroxymethylated by CH2O at the 4-position 1-substituted imidazoles react at the 2-position. Isoxazoles can be chloromethylated in the 4-position (63AHC(2)365). 

Imidazole, 2-amino-1 -methyl-4,5-diphenyl-tautomerism, 5, 368 Imidazole, 2-aroyl-mass spectra, 5, 360 synthesis, 5, 391, 402 UV spectra, 5, 356 Imidazole, 4-aroyl-synthesis, 5, 474 Imidazole, C-aroyl-UV spectra, 5, 356 Imidazole, aryl-nitration, 5, 396, 433 oxidation, 5, 433 Imidazole, 1-aryl-dipole moments, 5, 351 dearylation, 5, 449 ethylation, 5, 448 H NMR, 5, 353 hydroxymethylation, 5, 404 rearrangement, 5, 108 synthesis, 5, 390 thermal rearrangement, 5, 363 Imidazole, 2-aryl-chlorosulfonation, 5, 397 synthesis, 5, 475 Imidazole, 4-aryl-bromination, 5, 399 Imidazole, C-aryl-electrophilic substitution, 5, 432-433 nitration, 5, 433 Imidazole, N-aryl-reactions, 5, 448-449 structure, 5, 448-449 Imidazole, arylmercapto-... 

Imidazole, 5-hydroxy-1 -isopropyl-2-methyl-4-propyl-synthesis, S, 475 Imidazole, 2-hydroxymethyl-hydroxymethylation, S, 404 oxidation, S, 430 Imidazole, 4-hydroxymethyl-oxidation, S, 430 synthesis, S, 480, 484 Imidazole, 2-hydroxymethyl-4-methyl-synthesis, S, 484... 

Imidazole, 4-methyl-annular tautomerism, 5, 363 association, 5, 362 boiling point, 5, 362 bromination, 5, 398 deuteration, 5, 417 diazo coupling, 5, 403 hydrogen bonding, S, 350 hydroxymethylation, 5, 404 iodination, 5, 400 kinetics, 5, 401 mass spectra, 5, 358 melting point, 5, 362 methylation, 5, 364 sulfonation, 5, 397 synthesis, 5, 479-480, 482, 484, 489 Imidazole, 5-methyl-annular tautomerism, 5, 363 Imidazole, l-methyl-4-chloro-ethylation, 5, 386 Imidazole, l-methyl-5-chloro-ethylation, 5, 386 nitration, 5, 395... 

Acetylation of the hydroxymethyl imidazole 63 affords the corresponding ester (64), nitration (65) followed by hydrolysis gives intermediate 66, and reaction of this alcohol with potassium cyanate in hydrogen fluoride gives the carbamate ronidazole (67).16... 

Hydroxymethylation (formaldehyde) of nitro-imidazole 76 affords 77, which is oxidized to aldehyde 78. To prepare the other fragment for this convergent synthesis, reaction of epichlorohydrin with morpholine leads to the aminoepoxide 79, which is reacted with hydrazine to afford 80. Reaction of this substituted hydrazine with dimethyl carbonate affords oxazolinone 81 by sequential ester interchange reactions. Condensation of 81 with aldehyde 78 affords the antitricho-... 

Unsymmetric compartmental ligands that allow for the controlled synthesis of unsymmetric Ni2 or heterobimetallic NiM complexes have received particular attention.1876,1892 A wide range of such ligands derived particularly from 2-hydroxy-3-hydroxymethyl-5-methylbenzaldehyde and 2-hydroxy-3-hydroxymethyl-bromo-benzaldehyde has now been prepared and used for Ni com-plexation. These ligands have monopodal iminic pendent arms and either mono- or dipodal aminic pendent arms and the terminal donors of the pendent arms can be provided by pyridine, imidazole, and tertiary amino groups.1893-1897 Complexes are usually prepared by reaction of the requisite Ni11 salts with the preformed ligand. 

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]. 

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. ... 

Nishimura et that 169 may have the isomeric hydroxymethyl IH-imidazole structure. 

Durch Belichten waBriger Losungen von Formaldehyd und Ammonium-Salzen wie z. B. Am-moniumcarbonat werden in geringer Ausbeute Gemische aus Imidazol, 4(5)-Methyl-imidazol und (4(5) -Hydroxymethyl-imidazol erhalten10. 

Eine interessante Variante dieser Synthese ist die Herstellung von 4(5 j -Hydroxymethyl-imidazol aus Fructose28-31a 31b. Dabei unterliegt Fructose unter dem EinfluB der Base Ammoniak zu-nachst einer Retro-Aldol-Reaktion zu l,3-Dihydroxy-2-oxo-propan, das dann mit Ammoniak, Formaldehyd und Kupfer(II)-acetat zu 4(5)-Hydroxymethyl-imidazol weiterreagiert. 

Beim Einsatz von 3-Chlor-propansaure-imid-methylester wird unter den Reaktionsbedingun-gen das Chlor-Atom durch cine Amino-Gruppe substituiert und man erhalt 2-(2-Amino-ethyl)-4(5J-hydroxymethyl-imidazol (56%)61 ... 

Substituierte 4,5-Dihydroxy-4,5-dimethyl-4,5-dihydro-imidazole lagern sich unter dem Ein-fluB von Sauren in die entsprechenden 4(5)-Hydroxymethyl-5(4)-methyl-imidazole um416 (vgl. S. 34-37) ... 

Die C-Hydroxymethylierung mit Formaldehyd scheint bei 1-unsubstituierten Imidazolen iiber die N-Hydroxymethyl-Verbindungen zu verlaufen, die im Fall von 4 5)-Methyl-imidazol bzw. 2-Alkyl-4(5)-methyl-imidazolen unter milden Reaktionsbedingungen (Toluol, 50°) isoliert wer-den konnen730. Durch Behandeln mit konz. Salzsaure konnen diese 1-Hydroxymethyl-Verbin-dungen in 4(5)-Hydroxymethyl-imidazole umgclagert werden730. 

Imidazol selbst reagiert bei 130" mit waBriger Formaldehyd-Losung zu Produktgemischen ab. Als Hauptprodukte entstehen 1-Hydroxymethyl- (26%) und 1,2-Bis-[hydroxymethyl]-imidazol (18%)731. 

Aus 2-Mercapto-imidazol wird mit Formaldehyd/Dimethylamin in Essigsaure bei 4" 1-Hydro-xymethyl-2-mercapto-imidazol gebildet (71 %)732. Dagegen wird aus 2-Mercapto-4(5)-methyl-imidazol unter den selben Reaktionsbedingungen 4(5)-Hydroxymethyl-2-mercapto-5(4)-me-thyl-imidazol (82%) crhalten732. 

Neben den bereits in Band VI genannten Beispielen konnen auch 1-Alkyl-5-nitro-imidazole in 2-Stellung hydroxymethyliert werden (1 -Alkyl-2-hydroxymethyl-5-nitro-imidazole). Diese Umsetzung wird normalerweise in Dimethylsulfoxid mit Paraformaldehyd bei 120-130" durchgefuhrt746- 748. 

Methoxy-benzylthio)-l-methyI-imidazol wird unter ahnlichen Bedingungen ebenfalls se-lektiv in der 5-Position hydroxymethyliert, und man erhalt in 76% Ausbeute 5-Hydroxymethyl-4- (4-melhoxy-benzylthio )-l-methyl-imidazol752. 

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