Synthetic methodology for the preparation of N-hydroxysulfamides

A general methodology for the synthesis of N-hydroxysulfamides that allows stepwise introduction of various alkyl groups with control on the sulfamide nitrogens is reported. A convenient synthesis of a variety of substituted N-hydroxysulfamides from chlorosulfonyl isocyanate is reported. Alkyl groups can be introduced selectively on the N-Boc nitrogen of key intermediates 1a or 1b using the Mitsunobu reaction with alcohols. Subsequently the nitrogen carrying the silyloxy group can be alkylated under traditional conditions. Deprotection to the desired N-hydroxysulfamide can be achieved in high yields. Using this method, a number of structurally diverse N-hydroxysulfamides have been prepared. The usefulness of this methodology has further been demonstrated by the synthesis of more complex targets such as bis-hydroxysulfamide 5, and cyclic hydroxysulfamides 7 and 8.