Methylation of (1-azolyl)-1,4-dihydroxybenzenes

Nine new compounds have been prepared by methylation of monoazolyl and bisazolyl derivatives of 1,4-dihydroxybenzene. The azolyl substituents at positions 2 or 2,3 are 1-pyrazolyl, 3,5-dimethyl-1-pyrazolyl and 2-methyl-1-imidazolyl. The resulting compounds with one or two methoxy groups have been characterized by 1 H and 13 C NMR, by IR and by mass spectrometry. In two cases, both dimethoxy derivatives, the meso and d,l isomers have been identified.


Introduction
][3] In order to increase the steric demand of the OH groups, it was decided to transform them into OMe groups and to study the meso vs. d,l isomerism of the resulting compounds.

Meso vs. d,l isomerism
In the pyrazole series, the only compound that shows two isomers at room temperature is 11.
Since 12 presents only one series of signals, it can be concluded that two methoxy groups are necessary to hinder the rotation of the 3,5-dimethylpyrazolyl residues.In Tables 1 and 2, the most abundant isomer is reported first (only on this one the coupling constants have been measured) and the less abundant in a second row.The ratio, determined by 1 H NMR, is 92:8.According to our previous work, the most abundant should be the d,l.The proportions do not change with time, either the barrier is too high or 92:8 is the equilibrium mixture.
In the imidazole series, compound 14 presents also the meso/d,l isomerism, but here the mixture isolated by column chromatography is 63:37 (by 1 H NMR) and after 15 min the proportions are 47:53, after 2 days no variation is observed.The 13 C NMR spectrum of the first mixture has been recorded and the differences in intensity used to assign the signals (Scheme 2).Here again, the most abundant isomer corresponds to the d,l.If the CDCl 3 solution in evaporated, the residue dissolved again in CDCl 3 and the 1 H NMR spectrum recorded immediately, the d,l isomer is very largely predominant.Therefore, in the solid state only this isomer should be present.

Scheme 2. 1 H and 13 C NMR data of compound 14
Experimental Section General Procedures.Melting points were determined in a microscope hot stage apparatus and are uncorrected.Column chromatography was performed on silicagel Merck 60 (70-230 mesh) using the appropriate eluent.The R f values were measured on tlc aluminium sheets of silica gel 60 F254 (layer thickness 0.2 mm) with the solvent indicated in each case.Mass spectra were obtained with a Shimadzu QP-5000 spectrometer at 60 eV using the EI mode. 1 H NMR (400.13MHz) and 13 C NMR (100.62 MHz) spectra in solution were obtained using a Bruker DRX-400 instrument.Chemical shifts (δ) in ppm are referred to Me4Si.All spectra were recorded at 300 K.
In a three-necked round bottomed flask provided with a reflux condenser and magnetic stirring were placed 10.33 mmol of NaOH in 2.5 mL of water and 4.13 mmol of the corresponding 1,4dihydroxybenzene.Then, 8.26 mmol of dimethyl sulfate were added and the reaction warmed up to 70 °C during 1 h.If a precipitate appears it was filtered off.The solution was cooled down and extracted with CH 2 Cl 2 (3 x 20 mL) and the organic lawyer was dried over anhydrous sodium sulfate.The solvent is evaporated under reduced pressure and the residue (eventually together with the precipitate) is chromatographed using as eluent that indicated in each particular case.In some reactions, when the aqueous phase is neutralized with diluted acetic acid, a precipitate appears that corresponds to monomethylation products.