Efficacious N-protection of O-aryl sulfamates with 2,4-dimethoxybenzyl groups.
Sulfamates are important functional groups in certain areas of current medicinal chemistry and drug development. Alcohols and phenols are generally converted into the corresponding primary sulfamates (ROSO(2)NH(2) and ArOSO(2)NH(2), respectively) by reaction with sulfamoyl chloride (H(2)NSO(2)Cl). The lability of the O-sulfamate group, especially to basic conditions, usually restricts this method to a later stage of a synthesis. To enable a more flexible approach to the synthesis of phenolic O-sulfamates, a protecting group strategy for sulfamates has been developed. Both sulfamate NH protons were replaced with either 4-methoxybenzyl or 2,4-dimethoxybenzyl. These N-protected sulfamates were stable to oxidising and reducing agents, as well as bases and nucleophiles, thus rendering such masked sulfamates suitable for multi-step synthesis. The protected sulfamates were synthesised by microwave heating of 1,1'-sulfonylbis(2-methyl-1H-imidazole) with a substituted phenol to give an aryl 2-methyl-1H-imidazole-1-sulfonate. This imidazole-sulfonate was N-methylated by reaction with trimethyloxonium tetrafluoroborate, which enabled subsequent displacement of 1,2-dimethylimidazole by a dibenzylamine (e.g. bis-2,4-dimethoxybenzylamine). The resulting N-diprotected, ring-substituted phenol O-sulfamates were further manipulated through reactions at the aryl substituent and finally deprotected with trifluoroacetic acid to afford a phenol O-sulfamate. The use of 2,4-dimethoxybenzyl was particularly attractive because deprotection occurred quantitatively within 2 h at room temperature with 10% trifluoroacetic acid in dichloromethane. The four key steps in the protocol described [reaction of 1,1'-sulfonylbis(2-methyl-1H-imidazole) with a phenol, methylation, displacement with a dibenzylamine and deprotection] all proceeded in very high yields.
Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.
Tristan
T
Reuillon
Annalisa
A
Bertoli
Roger J
RJ
Griffin
Duncan C
DC
Miller
Bernard T
BT
Golding
D001593:Benzyl Compounds / Q000737:chemistry*; D015394:Molecular Structure; D013451:Sulfonic Acids / Q000138:chemical synthesis* / Q000737:chemistry
D001593:Benzyl Compounds; D013451:Sulfonic Acids; C005741:sulfamic acid