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Issue 37, 2012
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Efficacious N-protection of O-aryl sulfamates with 2,4-dimethoxybenzyl groups

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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.

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

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Publication details

The article was received on 01 Jun 2012, accepted on 31 Jul 2012 and first published on 02 Aug 2012

Article type: Paper
DOI: 10.1039/C2OB26057C
Citation: Org. Biomol. Chem., 2012,10, 7610-7617
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    Efficacious N-protection of O-aryl sulfamates with 2,4-dimethoxybenzyl groups

    T. Reuillon, A. Bertoli, R. J. Griffin, D. C. Miller and B. T. Golding, Org. Biomol. Chem., 2012, 10, 7610
    DOI: 10.1039/C2OB26057C

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