Reaction of N-alkylglycolurils with electrophilic reagents

Abstract

The N-hydroxymethylation, N-acetylation, and N-acetoxymethylation of mono-, di-, and trialkylglycolurils by reaction with the electrophilic reagents formaldehyde and acetaldehyde have been studied. General methods have been developed for the preparation of mono-, di-, and tri-Nhydroxymethylglycolurils by treatment of differently substituted N-alkylglycolurils with formaldehyde (as hemiformal in methanol) and the synthesis of di-N-and tri-N-acetyl-or N-acetoxymethylglycolurils via the electrophilic substitution of hydrogen atoms for an acetyl group at the nitrogen or oxygen atoms in the hydroxymethyl groups of glycolurils using acetic anhydride. The regioselectivity of the reaction of the 2-t-Bu-and 2-c-C 6 H 11 -glycolurils with formaldehyde has been shown to yield a 4,6-di(hydroxymethyl) derivative. It was found that the hydroxymethylation of 2,4-and 2,6-dialkylglycolurils occurs regioselectively with a stoichiometric ratio of glycoluril to hemiformal and permits preparation of their mono-and dihydroxymethyl derivatives. The enantiomeric analysis of the obtained compounds has been carried out for the first time using HPLC on chiral phases. X-ray analysis has been carried out on the previously unreported racemic 2, 6-diacetoxymethyl-4,8-dimethylglycoluril.

Identification of a Manufacturing Route of Novel CRF-1 Antagonists Containing a 2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine Moiety

“…Also, the introduction of DBU to replace K 2 CO 3 offered the advantage of a homogeneous reaction. Another breakthrough was the idea of a selective protection of the 2-imidazolidinone free nitrogen with an acetyl group, 15 to avoid competing arylation during the coupling. Following this strategy it was possible not only to completely suppress the side reaction but also to employ only 1.3 equiv of pyrazolyl compound 18 with a further reduction of 20% in the CoGs.…”

Glycolurils in α-ureido- and α-aminoalkylation reactions

“…3,9 Bis(N,N dimethylcarbamoyl) 1,3,5,7,9,11 hexaaza tetracyclo[9.2.1.0 5,13 .0 7,12 ]tetradecane 6,14 dione (8). A solu tion of tetra(hydroxymethyl)glycoluril 13 (5.24 g, 0.02 mol) and 1,1 dimethylurea 17b (3.52 g, 0.04 mol) in water (50 mL) was acidified dropwise with conc.…”

“…Melting temperatures were measured on a GALLENKAMP instrument (Sanyo). 2 Hydroxymethyl , 2,6 and 2,8 bis(hydroxymethyl) , and 2,4,6,8 tetra(hydroxymethyl) glycolurils 13-16 were prepared as described earlier 8. The course of the reactions was monitored by TLC.…”

Glycolurils in α-ureido-and α-aminoalkylation reactions 1. α-Ureidoalkylation of sulfamides with N-(hydroxymethyl)glycolurils

“…2 Hydroxymethyl , 2,6 and 2,8 bis(hydroxymethyl) , and 2,4,6,8 tetrakis(hydroxy methyl)glycolurils 7a-g were prepared as described earlier. 16 Synthesis of glycolurils 10a-d (general procedure). Appropri ate 4,6,8 trialkyl 2 (hydroxymethyl)glycoluril 7a,b (0.005 mol) and arenesulfonamide 8a,b (0.005 mol) were dissolved in metha nol (5 mL) and two drops of conc.…”