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Efficacious N-protection of O-aryl sulfamates with 2,4-dimethoxybenzyl groups

Lookup NU author(s): Tristan Reuillon, Annalisa Bertoli, Professor Roger Griffin, Duncan Miller, Professor Bernard Golding

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Abstract

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 (ROSO2NH2 and ArOSO2NH2, respectively) by reaction with sulfamoyl chloride (H2NSO2Cl). 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.


Publication metadata

Author(s): Reuillon T, Bertoli A, Griffin RJ, Miller DC, Golding BT

Publication type: Article

Publication status: Published

Journal: Organic & Biomolecular Chemistry

Year: 2012

Volume: 10

Issue: 37

Pages: 7610-7617

Print publication date: 02/08/2012

ISSN (print): 1477-0520

ISSN (electronic): 1477-0539

Publisher: Royal Society of Chemistry

URL: http://dx.doi.org/10.1039/c2ob26057c

DOI: 10.1039/c2ob26057c


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